a review of glutamate receptors ii - j-stage

J Toxicol Pathol 2008; 21: 133–173

Review

A Review of Glutamate Receptors II: Pathophysiology and Pathology

Colin G. Rousseaux1

1Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

Abstract: Seventy years ago it was discovered that glutamate plays a central role in brain metabolism and is abundantin the brain. Glutamate was then found to be the principal excitatory neurotransmitter in the brain. As stated in thefirst article of this series, there are three families of ionotropic receptors with intrinsic cation permeable channels: N-methyl-D-aspartate [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and kainate [Ka].Among these there are three groups of metabotropic, G protein-coupled glutamate receptors [mGluR] that modifyneuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers suchas diacylglycerol and cAMP. There are also two glial glutamate transporters and three neuronal transporters in the brain.Although glutamate is the most abundant amino acid in the diet, there is no evidence for brain damage in humansresulting from dietary glutamate. However, a Ka analog, domoate, is sometimes ingested accidentally in blue mussels;this potent toxin causes limbic seizures, which can lead to hippocampal and related pathology and amnesia. Endogenousglutamate may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumaticbrain injury by activating NMDA, AMPA or mGluR1 receptors. Glutamate may also contribute to chronicneurodegeneration in such disorders as amyotrophic lateral sclerosis and Huntington’s disease. In animal models ofcerebral ischemia and traumatic brain injury, NMDA and AMPA receptor antagonists protect against acute brain damageand delayed behavioral deficits. Other clinical conditions that may respond to drugs acting on glutamatergictransmission include epilepsy, amnesia, anxiety, hyperalgesia and psychosis. In this second part of this review, we willexplore those diseases in which the pathophysiology and pathology are associated, in part, with the glutamate system.(J Toxicol Pathol 2008; 21: 133–173)

Key words: glutamate, glycine, GABA, glutamate receptors, ionotropic, metabotropic, NMDA, AMPA, domoic acid, review, psychosis, Parkinson’s disease, Amyotrophic Lateral Sclerosis, Alzheimer’s disease, schizophrenia, Huntington’s disease, depression, excitatory amino acids, Multiple Sclerosis, stroke

Introduction and Overview

It is now recognized that three major categories ofs u b s t a n c e s a c t a s n e u ro t r a n sm i t t e r s . T h e s eneurotransmitters include amino acids (primarily glutamicacid, and glutamate [Glu], γ-amino butyric acid [GABA],aspartic acid [AP] and glycine [Gly]), peptides (vasopressin[VP], somatostatin [SS], neurotensin [NT], etc.), andmonoamines (norepinephrine [NE], dopamine [DA]) plusacetylcholine [ACh]1. Glu is the most common of theseneurotransmitters, as L-glutamic acid is present in mostfoods, found in either the free form or bound to peptides andproteins2. In fact, the Glu system is ubiquitous across mostanimal taxa3—Glu receptor genes have been found inplants4.

Received: 12 November 2007, Accepted: 26 May 2008Mailing address: Colin G. Rousseaux, 19 Klondike Rd., Wakefield, QC, J0X 3G0, CanadaTEL: 1 (819) 459-2998 FAX: 1 (819) 459-2960E-mail: [email protected]

The glutamatergic synaptic transmission in themammalian central nervous system [CNS] has beeninvestigated since the 1950s1,5,6. Realization that Glu andsimilar excitatory amino acids [EAA], such as domoic acid[DMA], mediated their excitatory actions via multiplereceptors preceded establishment of these receptors assynaptic transmitter receptors, in contrast to GABA and Glywhich are major inhibitory neurotransmitters3,7.

The most abundant molecular component of the Glusystem is N-acetyl aspartylglutamate [NAAG]8. It has beencalculated that a 70-kg man has a daily Glu intake of ~ 28 g,and a daily Glu turnover of ~ 48 g, of this compound derivedfrom the diet and from the breakdown of gut proteins.Despite this large turnover, the total pool of glutamic acid inblood is quite small, ~ 20 mg, because of its rapid extractionfrom and utilization by various tissues, particularly muscleand liver7,9. The human body contains about 10 grams offree Glu; brain 2.3 g, muscle 6 g, liver 0.7 g, kidneys 0.7 g,and blood 0.04 g10.

Glutamate receptors [GluR] perform a variety offunctions in the CNS and peripheral nervous systems [PNS]

134 Glutamate Receptor Biology

such as learning, memory11, anxiety, the perception of painas well as immune function12. They consist of two subtypes:ionotropic [iGlu] and metabotropic [mGlu].

Ionotropic glutamate receptors [iGluRs], sometimesreferred to as ligand-gated ion channels [LGIC], are a groupof transmembrane ion channels that open in response to achemical messenger, e.g., N-methyl-D-aspartic acid[NMDA], Kainate [Ka] and α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid [AMPA]. These LGICs aredifferent than voltage-gated ion channels or stretch-activatedion channels.

Metabotropic glutamate receptors [mGluRs] are activethrough an indirect metabotropic process. They aremembers of the Group C family of G-protein-coupledreceptors13–15. Molecular cloning techniques haveelucidated eight mGluR subtypes to date16, some of whichinclude alternately spliced variants13,14. The mGluRs havebeen divided into three groups based on sequence homology:Group I includes mGluR1 and mGluR5; Group II includesmGluR2 and mGluR3; and Group III includes mGluR4,mGluR6, mGluR7, and mGluR8

14. These three groups arefurther differentiated by their respective signal transductionmechanisms: Group I receptors stimulate phospholipase C[PLC], leading to phosphoinositide [PI] hydrolysis andintracellular calcium [Ca++] mobilization, whereas Group IIand Group III receptors are coupled to the inhibition ofadenyl cyclase14,17.

Activation of Group II mGluRs (mGluR2 and 3) orGroup III mGluRs (mGluR4, 6, 7 and 8) has been establishedto be neuroprotective in vitro and in vivo16, and for theNMDA iGluR18. mGluRs are found19 in pre- and post-synaptic neurons in synapses of the hippocampus,cerebellum20, cerebral cortex21, as well as other parts of thebrain and in peripheral tissues22,23.

Like other metabotropic receptors, mGluRs have seventransmembrane domains that span the cell membrane23.Unlike ionotropic receptors, metabotropic receptors are notdirectly linked to ion channels, but may affect them byactivating biochemical cascades. They can release Ca++

from intracellular structures where it is stored, such as theendoplasmic reticulum [ER]. Here, activation of mGluRscauses the production of inositol triphosphate, which in turnactivates receptors on the ER that open Ca++-permeablechannels. In addition to producing excitatory and inhibitorypostsynaptic potentials, mGluRs serve to modulate thefunction of other receptors, such as NMDA receptors, bychanging the synapse’s excitability15,16,23,24.

Endogenous Glu, by activating NMDA, AMPA ormGluR1 receptors, may contribute to the brain damageoccurring acutely after status epilepticus, cerebral ischemiaor traumatic brain injury25. Endogenous Glu may alsocontribute to chronic neurodegeneration in such disorders asamyotrophic lateral sclerosis [ALS]26, Alzheimer’s disease[AD]27, Parkinson’s disease [PD]28, Multiple sclerosis[MS]29, and Huntington’s disease [HD]30. For example, inanimal models NMDA and AMPA receptor antagonistsprotect against acute brain damage and delayed behavioral

deficits31,32.It is the purpose of this second part of this review (Part

II) to relate changes in these receptors to the pathology andpathophysiology of a number of diseases. In the first part ofthis review (Part I), the biological activities of the Glusystem were summarized and discussed. An effort has beenmade to address the toxicologic pathology of these receptorsin a number of diseases, particularly diseases of the CNS,whenever data are available.

Pathophysiology and Pathology related to Glutamate

As mentioned in the introduction, there is adequatedirect and circumstantial evidence for abnormal Glu and Gluanalogue transmission in the etiology and pathophysiologyof many neurological and psychiatric disorders13,32–48. Themechanism by which Glu is involved in the pathogenesis ofthese disease is probably through its excitotoxic effects49,which can be pronounced during acute events such asischemic stroke and trauma, or milder but prolonged inchronic neurodegenerative diseases such as AD, PD, HD andALS50–53. In addition there appears to be a role for Glu, Gly,and GABA and their regulation in manganese [Mn++],mercury [Hg++], and lead [Pb++] neurotoxicity54.

Glu also has been implicated in long-term plasticchanges in the CNS55–59, such as learning60 chronic pain,drug tolerance, dependence, addiction, partial complexseizures and tardive dyskinesia36,46,61,62. As more knowledgeregarding the specifics of all GluRs and their interactions,targeted drug development may be possible for thosediseases where Glu plays a central role in its pathogenesis63.

The CNS is not alone in its response to Glu-relatedeffects. Many tissues demonstrate Glu, GluRs, andglutamate transporters [GluT] activity, in addition to theCNS22. In fact, any tissue that has any central CNS,peripheral [PNS] or autonomic nervous system [ANS]components usually show Glu-related activity; however,these are not the only cell types to show such activity, e.g.,skeletal muscle64–112.

Glutamate or related EAAs in pathological processesGlu or related EAAs can cause neuronal injury as a

result of over excitation by excitotoxicity via exogenous andendogenous exposure1 1 3 , probably via the NMDAreceptor114. It is now known that GluRs are important in fetaldevelopment115 and act as mediators of inflammation andcellular injury through apoptosis and necrosis32,41–43,116,117,and as such have been suggested that EAA research may leadto a better understanding of the pathogenesis of these diseaseentities118.

GluRs have been reported to be associated withapoptosis and necrosis119, the former demonstrating noinflammation in conjunction with the cellular degenerationand the later is characterized by an inflammatory reaction,edema, and injury to the surrounding tissue following therelease of intracellular constituents that evoke a local

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inflammatory response120. The determinant as to whetherapoptosis or necrosis will occur under Glu stress is thedegree of damage to the mitochondria, where minor damageresults in apoptosis and severe damages producesnecrosis119. Regardless of the mechanism of cell death, Ca++

influx is central to neurodegeneration121.Inflammation, a hallmark of necrosis, causes marked

alterations in regional cell membrane transport andintracellular glutamine122. Here, the increased endogenousglutamine biosynthesis cannot keep up with the new demandresulting a deletion of the glutamine pool, as the liver andother viscera increase their uptake of glutamine duringinflammation122. As Glu ameliorates endotoxic shock andasthma through the inhibition of cytosolic phospholipaseA(2) (cPLA(2)) activity, it is possible that reduced availableGlu may increase the inflammatory response. Because ofthese observations, clinical treatment with Glu has beensuggested123.

As inflammation is often part of the neoplastic processand the glutamatergic system has been implicated in tumourbiology124,125, investigation of the glutamatergic system withrespect to cancer biology has been explored to someextent126. In fact, paraneoplastic ataxia in patients withgynecologic cancer, breast cancer, lung cancer, or Hodgkin’sdisease has been associated with autoantibodies againstGluRs aberrantly expressed by the tumor cells1 2 7.Paraneoplas t ic effects are numerous and includeneurological, muscular, dermal, renal and bone marrowdetrimental effects.

Not al l effects on Glu, GluRs and GluTs areendogenous, or exogenously obtained via the diet. Anumber of reptilian and arachnid venoms have be show toaffect their toxicity via inhibition of the activity of GluRs.For example, Araneus gemma, Neoscona arabesca, andArgiope aurantia all have shown inhibitory effects on thesynaptic Glu releasing membrane128.

1. NeuronsApoptosis and necrosis in neurons often occurs due to

osmotic damage due to the influx of Ca++ and waterparticularly in mitochondria129. Because the iGluRs are ion-gated channels selective to sodium [Na+], potassium [K+],and Ca++, any sustained stimulation of the GluRs results inentry of Ca++ resulting in death of neurons37,38,41–43,75,130. Theintracellular increase in Ca++ concentration in neuronsactivates phospholipases, protein kinase C, proteases,protein phosphatases, nitric acid synthases131 and thegeneration of free radicals32,35,37,38,41,43,49,76–78,88,91,132–136.

Activation of phospholipase A2 results in the generationof arachidonic acid, its metabolites and platelet-activatingfactors [PAF]. PAF increase the neuronal Ca++ levels bystimulating the release of Glu and corresponding increasedinflux of ions through iGlu ion-gated channels137.

Not only the release of Glu is increased by thisstimulation, but also arachidonic acid potentiates NMDAevoked currents and inhibits the reabsorption of Glu intoastrocytes and neurons. These events further exacerbate the

situation by a positive feedback mechanism where freeradicals are formed during arachidonic acid metabolism,leading to further phospholipase A2 activation. The result isan increased concentration of extracellular Glu, whichcontribute to the sustained activation of the GluRs37,38,49,138.

As a consequence of this sustained activation, cysteinetransport is inhibited causing a decrease of intracellularreducing sulphydryl groups and the generation of oxygenfree radicals, which results in death of neurons through lackof cation control and influx of Ca++ 117. In addition toenzymes of the cell cytosol, free radicals contribute to theDNA fragmentation, and the activation of nuclear enzymessuch as endonucleases are also activated by increase of Ca++

resulting in apoptosis. On the other hand, if severe damageresults in rupture of lysozomes and extracellular release ofintact and enzymatically modified cellular organelles,necrosis and subsequent inflammation will occur120,139.

Nitric oxide [NO] has also been shown to be aneurotransmitter in the parasympathetic postganglionicneurons and in preganglionic sympathetic neurons140. Theincreased concentration of neuronal intracellular Ca++ alsoraises the NO concentration via the calmodulin activation ofnitric oxide synthetases [NOS]. An increase in NO generatesmore oxygen free radicals that further damage the integrityof the cell membrane140. Because the NO is Ca++- andcalmodulin-dependent and the AMPA receptors are Ca++

permeable, it is possible that NO is activated through AMPAreceptors.

Neurons are not the only cell type in the nervous systemto be damaged by high concentrations of Glu, probably inconjunction with NO141. Oligodendrocytes play animportant role in axonal conduction in the CNS and aresensitive to oxidative toxicity induced by Glu in the absenceof iGluR. The sensitivity to Glu in the absence of GluRmight indicate that olidendroglia are more sensitive to Gludamage than neurons.

2. OligodendrocytesFunctional NMDA receptors recently have been

reported in brain glia, astrocytes, and oligodendrocytes142,143.Glial and neuronal NMDA receptors are functionally andstructurally different; the glial receptors are weakly, if at all,sensitive to the extracellular magnesium [Mg++] block,which may indicate a predominant expression of the NR3receptor subunit144. In the cortex, astroglial NMDAreceptors are activated upon physiological synaptictransmission, but the physiological relevance of NMDAreceptors in the white matter remains unknown. Theiractivation upon ischemia triggers Ca++-dependent damage ofoligodendrocytes and myelin143, a finding that hasimplications for many central nervous disorders such as MS.

Oligodendrocytes are also vulnerable to the results ofover stimulation of iGluRs, such as Ka and AMPA. AMPAtoxicity is short lived as rapid desensitization of AMPAreceptors occurs145. Glu also induces oxidative stress andKa-AMPA receptor stimulation via activation of mitogenprotein kinase [MAP kinase] pathway, as well as the


transcription factor ELK, which incidentally is a possibleregulator of c-fos expression146.

However, MAP kinase inhibitors only protect againstinjury from Glu-induced oxidative stress. Oligodendrocytesare sensitive to oxygen-glucose deprivation injury as well, ina MAP kinase dependent fashion. Hence Glu toxicity maybe operative in neuropathological conditions that disruptneuronal-oligodendrocyte interactions in axons, e.g., MSand ischemia-reperfusion injury145, methyl mercury147 andammonia toxicity148.

NO is an import molecule in oligodendrocyte injury,and oligodendrocytes have more complex interactions withNO than initially suspected. Historically, oligodendrocyteswere seen only as targets of high NO levels released fromother cells149,150. However, small numbers of microglialcells are inducible for nitric oxide synthase type II [NOS-2]e x p r e s s i o n v i a N O S - 2 i n p r i m a r y c u l t u r e s o foligodendrocytes stimulated by cytokines. The present viewis that immature oligodendrocytes express NOS-2, but thatthey do not when they are mature, which raises questionsabout the regulation of NOS-2 expression in microglia thatmay become oligodendrocytes. Recently, it has beensuggested that that constitutive nitric oxide synthase type II[NOS-3] expression may play a key role in oligodendrocyticinjury due to its activation by Ca++, in interaction withpathways mediating Glu toxicity151.

3. AstrocytesAstrocytes also have been shown to play an important

role to play in Glu neurotoxicity152. A co-culture systemcombining cerebellar cells and astrocytes has been used toinvestigate the astrocytic control of Glu toxicity153. The co-culture of astrocytes with cerebellar neurons enhancesuptake of Glu by astrocytes, but inhibition of Glu uptake inthis system leads to death of neurons, indicating thenecessity of Glu for normal neural functioning. However, inthe presence of the Glu uptake inhibitor, no observedincrease of Glu in the cultures, compared with those thatwere not co-cultured, indicates an interaction of astrocytesand neurons in Glu toxicity.

These findings indicate that neurons become moresusceptible to Glu toxicity in the presence of astrocytes andthus become dependent on astrocytes for prevention of Glutoxicity. Astrocytes treated with conditioned medium fromcerebellar cells did not show an increase in Glu uptake butastrocytes exposed to neuron conditioned medium weretoxic to cerebellar cells, due to Glu present in the medium.In fact, concentrations of Glu required to produceneurotoxicity in the absence of astrocytes was 100 times thatrequired to produce neurotoxicity in the presence ofabundant astrocytes154.

These observations suggest that a soluble factorreleased by neurons, signals to astrocytes that neurons arepresent and stimulates a signal back to neurons, whichcauses an increased sensitivity to Glu toxicity1 5 3.Alternatively, GluTs could be involved, where a malfunctionin GluTs may lead to an excessively high extracellular Glu

concentration resulting in neurodegeneration caused by Gluexcitotoxic effects155.

Central nervous system disordersNeurons that contain Glu, also contain GluRs and

make up an extensive network throughout the cortex,hippocampus, striatum, thalamus, hypothalamus, cerebellum,and visual and auditory system in the CNS43,156–159 can befound in both grey and white matter159. As a consequence,Glu neurotransmission has been recognized as essential forcognition, memory, movement and sensation; especiallytaste, sight, and hearing43. In addition, Glu has been shownto cause a loss in human cerebral endothelial barrier integritythrough activation of NMDA receptor160,161.

A broad range of chronic neurodegenerative diseaseslisted above are now believed to be caused, at least in part,b y t h e e x c i t o t o x i c a c t i o n o f G l u a n d a s p a r t a t e[Asp]43,156,157,162–164. It is possible that Glu and Aspexcitotoxity causes memory loss, confusion, and mildintellectual deterioration that frequently occur in late middleage to old age32.

Glu clearly plays an important role in neuronaldifferentiation, migration and survival in the developingbrain. Its activity is largely through facilitating the entry ofCa++ 165,166. Blockade of NMDA receptors during theprenatal period with compounds such as phencyclidine[PCP] or ethanol167–170, can induce apoptosis in vulnerableneurons, the select ivi ty of which depends on thedevelopmental stage171. Such degeneration is probablyresponsible in part for the neurological developmentsyndromes including fetal alcohol syndrome.

1. Exogenous glutamate and neurodegenerationGlu has three distinct possible mechanisms of action in

acute or chronic neurodegenerative processes resulting fromagonist effect on NMDA, AMPA, and Ka or Group Imetabotropic receptors32. These mechanisms includeexogenous Glu, or related compounds acting on GluRs, canbe consumed in the diet and damage the brain; endogenousGlu released from neurons can contribute to acuteneurodegeneration occurring in relation to cerebral ischemiaor traumatic brain injury; and activation of Glu receptorscontributes to the process of cell death in chronicneurodegenerative disorders32. In the case of exogenous Gluand other analogues poisoning, the first process is mainly ineffect.

Monosodium glutamate: There is general controversyregarding toxicity of monosodium glutamate [MSG]. In thelate 1960s numerous case reports appeared in the scientificliterature describing a complex of symptoms which came tobe known as the Chinese restaurant syndrome [CRS]because they typically followed ingestion of a Chinesemeal90. The most frequently reported symptoms includeheadache, numbness, tingling, flushing, muscle tightness,and generalized weakness. Investigations have mainlyfocused on MSG as the causative agent.

More recently, the term MSG symptom complex has

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been used instead of CRS. The prevalence of CRS is notreally known but is suggested that it affects between one andtwo percent of the general population. The reports of MSG-triggered CRS were followed in the early 1980s by reports ofa possible association between MSG and the triggering ofbronchospasm and bronchoconstriction in small numbers ofasthmatics. While a number of mechanisms have beenproposed to explain how MSG might trigger the variousreported reactions, none has been proven, and very littlefollow-up research has been conducted to investigate furtherany of the proposed mechanisms172.

There is no convincing evidence that MSG is asignificant factor in causing systemic reactions resulting insevere illness or mortality173,174. Studies conducted to dateon CRS have largely failed to demonstrate a causalassociation with MSG. Symptoms resembling those of CRSmay be provoked in a clinical setting in small numbers ofindividuals by the administration of large doses of MSGwithout food175–177. However, such affects are neitherpersistent nor serious and are likely to be attenuated whenMSG is consumed with food178. In terms of more seriousadverse effects such as the triggering of bronchospasm inasthmatic individuals, the evidence does not indicate thatMSG is a significant trigger factor172. However, due to theindividual nature of hypersensitivity, it would not be wise torule out the possibility that some susceptible individuals areaffected even though reviews suggest that there is noconsistent evidence to suggest that individuals may beuniquely sensitive to MSG179.

Contrasting these findings that point to are the definiteeffects of MSG on organ systems in experimental models. Inthe CNS, MSG has been shown to cause neuronal celldeath180, a deficit in hippocampal long term potentiation[LTP] in rats181, learning disabilities182, behavioral deficits inadult rats183, delayed coordination of neonates184, retinaldamage185, hepatic, and renal toxicity186. It should be notedthat very large doses of MSG, which could be consideredtoxic, were used in these experiments. As we have seen thatGlu has a double action—neurotransmitter at low doses andneurotoxicant at high doses—extrapolation of these resultsto the real life situation should be done with extreme caution.

Domoic acid: The classical CNS effects of poisoningwith an exogenous Glu analog domoic acid [DMA], anagonist of non-NMDA receptor subtype including Kareceptor187,188, has allowed detailed neuropathologicalevaluation of animal and human tissues94,132,187,189. As withother excitotoxins, DMA causes neurotoxicity via Ca++

influx into neurons190. In neuropathological studies in fourelderly men who succumbed to the toxin after days revealedextensive bilateral limbic system pathology with neuronalloss in cellular zones of hippocampus (CA1, CA3, dentategyrus), amygdala, claustrum, septal area, thalamus andinsular and sub frontal cortex32.

The altered morphology seen following DMA toxicity isa consequence seizure activity, involving mainly the limbicsystem, rather than the effect of a direct excitotoxic action ofdomoate, as almost all of the pathology, except for CA3 cell

loss and sometimes some amygdala damage, is prevented bythe administration of an Ka/AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione [NBQX]191. It is likely that only the CA3 neurons dieas a direct result of the excitotoxic action of domoate, hencethe retrograde amnesia often noted in those poisoned withDMA. The morphology following direct injection of DMAinto the hippocampus has been characterized by severeneuronal necrosis192, although this experiment did not modelthe natural exposure route and dose.

Neurolathyrism: β-N-Oxalylamino-L-alanine [BOAA],also referred to as β-N-oxalyl-α,β-diaminopropionic acid [β-ODAP], is a toxin found in chick peas thought to beresponsible for the syndrome of neurolathyr ism.Neurolathyrism, which causes a motor disability as a resultof loss of upper motor neurons is seen predominantly inmalnourished young men and can have an acute or semiacute onset193.

BOAA is a selective agonist for AMPA receptors andcan cause excitotoxic cell death in neonatal rodents or intissue culture194. However, BOAA does not produce thespecific pathology of neurolathyrism in rodents or primates,although a transient neurological syndrome has beendescribed in monkeys32. It is possible that the humansyndrome depends on some vitamin or other deficiency thatimpairs mitochondrial metabolism and renders neuronsunusually vulnerable to an AMPA agonist.

2. Possible exogenous glutamate toxicityAmyotrophic lateral sclerosis of Guam [ALSG]: Glu

and GluRs probably have a role in the development ofamyotrophic lateral sclerosis of Guam [ALSG]. β-methylamino-L-alanine [BMAA], present in the fruit of thecycad plant that grows in Guam, has been proposed as thedietary toxin responsible for ALSG195. BMAA is notdirectly excitotoxic, but becomes toxic in the presence ofbicarbonate196. In rats, acute excitotoxicity is seen in thecerebellum after administration of very high doses (1–4 g/kg) of BMAA, probably mediated through the excitotoxiceffects of Glu, GluRs, and GluTs; however, the low level ofconsumption and the very long latent period make itextremely unlikely that BMAA is acting as an excitotoxin toproduce ALSG. The question of how cycad toxicity andALSG relate, and the mechanisms by which such lesionsoccur is unclear and is still being explored195,196.

Mitochondrial toxins and excitotoxic lesions in thestriatum: Another mechanism whereby activation of GluRsleads to neurodegeneration involves mitochondrial toxins,such as malonate and 3-nitropropionic acid [3-NPA]. 3-NPA inhibits succinate dehydrogenase and impairs electrontransport and therefore adenosine triphosphate [ATP]synthesis. A consequence of impairing the electron transportchain is that the neuron becomes increasingly vulnerable toexcitotoxic and free radical damage197, and cannotcompensate for Ca++ overloads.

3-NPA is a secondary metabolite of the fungiArthrinium sp. that grows on sugar cane. It produces a


pattern of selective damage in the striatum very similar tothat seen in HD, with preferential loss of GABAergicneurons198–200. Activation of NMDA receptors clearly playsa part in this selective neuronal degeneration becauseNMDA receptor antagonists can prevent the damageinduced by systemically administered 3-NPA200. It ispossible that reduction in resting membrane potential leadsto reversal of the Mg++ block so that low concentrations ofGlu activate the NMDA receptor directly32.

3. Endogenous glutamate and acute neurotoxicityExogenous Glu acting on AMPA, NMDA and mGluR1

receptors probably plays an important role in necrosis, inextreme stress and apoptosis under lesser stress, subsequentto status epilepticus, cerebral ischemia, perinatal asphyxiaand traumatic brain injury resulting138. As far as the neuronis concerned, the difference between apoptosis and necrosisis moot, although the inflammation associated with necroticcells will impact the surrounding tissue120.

The primary mechanism, as was described previously,involved in neuronal death is via ionic disequilibrium relatedto the excessive entry of Na+ and Ca++ through LGICs suchas NMDA, AMPA and Ka. Raised intracellular Ca++

concentrations activate various enzymes includingproteases, phospholipases, nitric oxide synthases orendonucleases, which contribute to cell death by a number ofmechanisms201. There is a complex interaction between theionic changes, altered energy metabolism, the poisoning ofmitochondria and oxidative or free radical-mediateddamage202, leading to neuronal death. Probably the simplestoutcome of these interactions is the production of Ca-lipid“soaps”, which prevent oxidative phosphorylation.

Selective antagonists can be used to show the role of theLGICs; thus, NMDA receptor antagonists of all types (GluRcompetitive antagonists, Gly site competitive antagonists,open channel blockers and selective antagonists actingpreferentially on a polyamine site or on the NR2B subunit ofthe NMDA receptor) protect against ischemic braindamage203.

4. Metabotropic glutamate receptors (mGluRs) and neurodegeneration

The predominant effect of Group I GluR activation isexcitatory. Agonists, such as 1S , 3R-1-amino-1,3-cyclopentanedicarboxylate and 3,5-dihydroxyphenylglycine,act on mGluR1 or mGluR5. When mGluR agonists areinjected focally into the brain, they produce epileptic activityand focal neurodegeneration confirming that Glu is anEAA204. This focal stimulation is probably caused by areduction in several K+ conductances producing membranedepolarization with potentiation of NMDA receptor-mediated conductance changes and excitotoxicity205.

There is, however, one Ca++ sensitive K+ channel that iso p e n e d b y m G l u R 1 a c t i v a t i o n l e a d i n g t ohyperpolarization206,207. Activation of Group I mGluRcontributing to cell death following cerebral ischemia andtraumatic brain injury has been supported by research

findings. These reports show that Group I mGluRantagonists can be neuroprotective in model systems25.

A variety of effects have been described in cell cultures.In hippocampal cells expressing Group I mGluR, but notiGluRs, a protective effect of Glu is seen against oxidativestress and against glucose deprivation208. In addition, Glupre-exposure has the effect of up-regulating mGluR1 andmGluR3. In co-cultures of neurons and astrocytes, activationof Group II receptors on astrocytes is neuroprotective viarelease of a neurotrophic factor, transforming growth factorβ [TGF-β]209,210. NAAG, the endogenous mGluR3 agonist,also is neuroprotective against striatal quinolinate lesions211

and against NMDA excitotoxicity in mixed corticalcultures212. TGF-β and Group II mGluR agonists alsoprotect against apoptosis induced by β-amyloid213.

5. Chronic neurodegenerationThe Glu synapse is a potential target for intervention in

a very wide range of neurological and psychiatric disordersincluding epilepsy, motor neuron disease [MND], HD, AD,PD, stroke and traumatic brain injury, psychiatricdisturbances, and pain214,215. It has been proposed that theneurodegeneration seen in these late onset neurologicaldisorders, is at least partially dependent on endogenous Gluactivating NMDA or AMPA receptors.

Motor neuron diseases and amyotrophic lateral sclerosis:Motor neuron disease [MND]26 may involve defective GluTand enhanced AMPA receptor activation216–218. Therefore,anti-Glu strategies have been proposed and Riluzole hasbeen shown to decrease mortality219. Excitotoxicity doesplay a role in the degeneration of spinal motor neurons inindividuals with ALS220,221. In fact low concentrations ofGlu determined in cerebrospinal fluid of patients (only 2-fold increase compared with controls) induce apoptosis incultured spinal motor neurons222.

AMPA receptors on spinal motor neurons [SPN] areinvolved in several types of MND216,223 and probablymediate their activity through permitting increasedintracellular accumulation of Ca++ 224. iGluRs are not theonly receptor group implicated in the disease, althoughinterpretation of the effect of the mGluR is difficult.Inhibition of mGluR is claimed to have a protective effect225,but it also reduces expression of mGluR2 mRNA in T-celllymphocytes is seen in individuals with the active disease226.The explanation for the differences in these studies probablycan be attributed to the cell types examined227.

In patients with MND, there appears to be a reduction inthe expression of mGluR1, a glial GluT, in the spinal cordand brain regions showing loss of motor neurons [MN]228

and defective editing of mRNA encoding the GluR2 subunitof Glu AMPA receptors in affected MNs from individualswith ALS229. The modification of these AMPA receptorsaggravates the disease230, probably through the increase infree Glu. In addition, mGluRs are also involved in theexcitotoxicity. Loss of the mGluR-mediated regulation ofGlu transport in chemically activated astrocytes doesexacerbate MN toxicity231.

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In organ cultures of spinal cord, Glu transport inhibitorscause degeneration of MNs and AMPA receptor antagonistssuch as GYKI 52466 can prevent this degeneration232,233.AMPA receptor antagonists protect against the toxic effectsof mutations in Cu++ and Zn++ superoxide dismutase [SOD]seen in cultured mouse neurons234.

Recent studies suggest that MN death may be non-cellautonomous, with cell injury mediated by interactionsinvolving non-neuronal cells, such as microglia andastrocytes235. In fact, primary MN cultures with microgliaactivated by lipopolysaccharide [LPS] or immunoglobulin G[IgG] immune complexes from patients with ALS inducedMN injury in the presence of Glu. Addition of astrocytes toco-cultures of MN and activated microglia prevents MNinjury by removing Glu from the media. Increasedexpression of Glu is probably mediated by a decrease inexpression mGluR1 by astrocytes236. These data suggest thatfree radicals released “Reactive Oxygen Species” [ROS]from activated microglia may initiate MN injury byincreasing the susceptibility of the MN AMPA/Ka receptorto the toxic effects of Glu.

Huntington’s disease: Huntington’s disease [HD],which was first described by George Huntington in 1872,involves the extrapyramidal motor system, and ischaracterized by chorea, a dementia that is progressive, andother psychiatric symptoms30. In terms of brain pathology,GABAergic medium spiny striatal neurons are mostaffected, resulting in atrophy of the caudate nucleus,putamen, and globus pallidus; there is also pronouncedatrophy of the cerebral cortex237,238. The neuronal loss in thestriatum is accompanied by pronounced gliosis.

The vulnerable striatal neurons contain encephalin,dynorphin, and substance P, and primarily innervate thesubstantia nigra and globus pallidus. Medium sized spinyneurons containing somatostatin, neuropeptide Y, andNADPH diaphorase, in addition to cholinergic interneuronsand parvalbumin containing GABAergic neurons, which arerelatively spared239. In the cerebral cortex, large neurons inlayer VI are the most affected, with smaller amounts ofdegeneration seen in layers III and V238–240. Neurons mayalso be lost in the thalamus, zona reticulata of the substantianigra, superior olive, lateral tuberal nucleus of thehypothalamus, and deep cerebellar nuclei239,241. There isalso an overlapping pattern of neurodegeneration ofGABAergic efferent projection neurons with the progress ofthe disease, accompanied by the loss of cannabinoid [CB]receptors throughout the basal ganglia242.

It has been demonstrated that the underlying cause ofHD is the expansion of a CAG repeat sequence in the firstexon of a gene on chromosome 4p16.3, which encodes theprotein huntingtin242–244. CAG is the codon for glutamine (Qin the single letter code for amino acids)245. The normalrange for the number of Qs in the polyglutamine tract[polyQ] is between six and 34, with disease being foundwhen polyQ is greater than 40.

Interestingly, within the HD genome, expansion oftrinucleotide repeats appears not to be limited solely to the

huntingtin gene. The allelic frequency distributions for twoother genes containing such repeat sequences (SCA1 andFRDA) are shifted towards larger alleles compared withhealthy controls, which suggests that a common mechanismcaused expansion in all three genes246. The expanded CAGrepeat is transmitted predominantly through the male germline in humans and transgenic mice, and the size of the CAGrepeat was influenced by the sex of the offspring fromidentical fathers. Thus, male offspring had expandedrepeats, whereas the opposite was seen in females. Thisfinding led to the hypothesis that X and Y chromosomalencoded factors influenced embryonic DNA repair andreplication247. Furthermore, within striatal cells, expansionbiased changes were shown to increase with age, suggestingthat non-replication based mechanisms may also contributeto CAG repeat instability248.

Attention to excitotoxicity via the NMDA and Kareceptors in HD has been given249–252 and now much of theintracellular signaling cascade underlying excitotoxicity inHD has been pieced together. Key players in excitotoxicityare the NMDA253 and Ka receptors, post-synaptic densityprotein 95 (PSDP-95), mixed lineage kinase [MLK], and c-Jun-N-terminal kinase [JNK].

GluR stimulation is involved in MLKl activation254,whereas JNK3 activation has been linked to apoptosis255.More neurons display desensitizing AMPA currents in thepresence of cyclothiazide [CTZ], indicating increasedexpression of “flop” splice variants, whereas the majority ofwild-type cells express the “flip” variants of AMPA receptorsubunits in R6/2 mice256. NMDA peak currents also aresmaller in R6/2 pyramidal neurons and currents are smaller inthe presence of Mg++. Altered GluR function couldcontribute to the changes in cortical output and may underliesome of the cognitive and motor impairments in the R6/2animal model of HD256.

Now the connection between these processes and theroles of huntingtin and excitotoxic proteins is becomingclearer. PSDP-95 is a scaffold protein, which binds toseveral intracellular proteins and possesses guanylatecyclase activity. It binds via repeat units in its structure,termed PDZ domains, to the NMDA receptor and plays apivotal role in regulat ing synaptic plast ici ty andsynaptogenesis257. Specifically, PSDP-95 binds to the NR2NMDA receptor and Ka receptor, GluR6, subunits.

Variant huntingtin with expanded polyQ tracts interferewith the binding of PSD-95 to NMDA and Ka GluR, causingboth receptors to become hypersensitive258,259, therebyallowing increased Ca++ influx via specific uptakepathways260. In turn, the MLK isoform, MLK2

261 isactivated, causing activation of MAP4 and MAP7 kinasesand stress signaling kinase [SEK1], and consequentlyJNK2

261,262.Activated JNK2 phosphorylates the N-terminal region

of c-Jun, which is one half of the transcription factoractivator protein AP1, thus modulating gene transcription.Activated JNK also phosphorylates the C-terminal region ofMLK2. This step appears to be crucial in the triggering of


apoptotic cell death30. Co-transfection of a dominantnegative MLK2 blocks apoptotic cell death induced byvariant huntingtins263.

Alzheimer’s disease: The classical neuropathologicalchanges seen in AD include cortical atrophy, loss ofcholinergic cells in the nucleus basilis, and regionalhistopathological changes in the brain27. Pathologicalchanges include neuritic plaques, neurofibrillary tangles[NFTs], neuropil threads, and granulovacuolar neuronaldegeneration. Neuritic plaques have a central core thatin c l u de s β - a m y l o id , p r o te og l yc a n s , a po E , α 1 -antichymotrypsin, and other proteins264. Accumulation of β-amyloid activates macrophages and microglia, producinginflammation that further accelerates neuronal damage265.

The NFTs are paired helical neurofilaments in neuronalcytoplasm that consist of abnormally phosphorylated tau [τ]protein and ubiquitin27,264. In its normal form, τ functions inthe assembly and stabilization of microtubules that guidetransport of organelles, glycoproteins, and other importantmaterials through the neuron264. Although some aspects ofAD pathology are found in normal aging, the density ofneuritic plaques and NFTs increases as AD progresses andcan be distinguished from those of age-matched normalpeople265.

AD was once thought to result from a cholinergicdeficit alone, but now it is recognized that this view is oversimplistic266,267. Studies using human neocortical tissue haveshown that multiple neurotransmitters are involved indetermining the amplitude of individual postsynapticcurrents and, consequently, the electrophysiology of thehuman cerebral cortex268. These neurotransmitters includeGlu, DA, NE, and serotonin (5-hydroxytryptamine [5-HT]),and have been shown to be reduced or dysregulated in AD.The interactive regulation of actions of these transmitterscomplicates our understanding of the control and modulationof neuronal activity, but an understanding of how theseprocesses work together may eventually permit us tounderstand the mechanism of the progression of AD269.

Currently, the neurotransmitter systems most studied inthe pa thogenes i s o f AD are the chol ine rg ic andglutamatergic systems27,270. In the glutamatergic systemsboth iGluR and mGluR seem to play a role in AD as themGluR has been associated with increased amyloidprecursors in individuals with AD271. However, therelationships among the iGluR and mGluR are probablycomplex272.

In sporadic Alzheimer’s disease [SAD], Glu andglutamine concentrations fall because it acts a substitute forlack of glucose early in the disease. In fact, Glu-glutaminecycling is found in the brains of individuals who have diedshowing clinical signs of AD701. In contrast, the affect onGluR density is minimal, indicating an excessive activationof the glutamatergic neurotransmitter system, particularlyvia the NMDA receptor, which can mediate endogenousexcitotoxicity273. NMDA plays a distinct role in AD269.

The NMDA receptor serves as a gating switch for themodification of major forms of synaptic plasticity so it plays

a crucial role in certain types of learning, memory formation,and the consolidation of short-term memory into long-termmemory274. It is a large macromolecular complex275 thatrequires Glu and the modulatory agent Gly to be presentbefore activation of the receptor can take place276.

Mg++ can gate Glu-activated channels277 by blockingthe NMDA ion channel under the conditions of a restingmembrane potential at approximately –70 mV. This blockis removed by depolarization of the cell membrane to about–50 mV276. Dysregulation of NMDA receptor function hasbeen implicated not only in the pathology of AD278, but alsoin the pathogenesis of various other neurodegenerativedisorders279. Glu and GluR play an important part in AD269.

Neuroimaging studies have shown that Glu andglutamine are reduced in the brains of patients with AD280,which indicated that the local dysregulation of Glu mightcontribute to Glu neurotoxicity in AD269. One of the primarynonvesicular sources of extracellular Glu in AD appears toarise from a dysfunctional cystine-Glu antiporter281. Undernormal physiologic conditions, the antiporter is negativelyregulated by mGluR and Glu transporters, which ensure thatthe right amount of Glu is released. In addition, β-amyloidaccumulation in AD has been shown to inhibit Na+-dependent Glu uptake through oxidative inhibition of theGlu transporter282, which may increase local extracellularconcentrations of Glu283.

Memantine is a weak Glu antagonist and has beenshown to improve learning and memory in animal modelsand in patients with moderate to severe AD, whereas high-affinity NMDA receptor antagonists may provide aninhibition of NMDA receptors that is too strong fortherapeutic benefit279,284,285. Achieving the optimal balanceof Glu stimulation without excitotoxicity is an importantgoal for achieving the optimal treatment of patients with AD.It is using this concept of balance that memantine, anoncompetitive agonist with a relatively low to moderateaffinity for NMDA receptors was developed for someneurodegenerative diseases286,287,291. It does not bind to theagonist-binding site but instead blocks the open channels ina m a n n e r t h e N M D A r e c e p t o r , an d i s v o l t a g edependent288,289,290.

Further elucidation of interactions of the cholinergicand Glu systems is warranted. Although cholinergic andglutamatergic interactions are quite complex, nonclinicalexperiments have helped us interpret how these complexsystems interact292. Activation of nicotinic receptors locatedon presynaptic glutamatergic neurons stimulates Glu releaseand increases the NMDA receptor activity on postsynapticneurons292–294. Activation of presynaptic nicotinicacetylcholine receptors in the presence of extracellular Ca++

can initiate multiple forms of enhanced glutamatergicsynaptic transmission in rat hippocampal neurons, thetemporal relationship of which suggests that the loss of thecholinergic synaptic mechanisms that modulate the gain andfidelity of hippocampal synaptic transmission maycontribute to the cognitive deficits seen in AD294.

In addit ion, our understanding of the role of

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acetylcholine [ACh] in learning and memory has beenfurther enhanced by studies of human and guinea pig corticalpyramidal neurons268. Results from these studies suggestthat the long-lasting effects of ACh on specific ionic currentsmay facilitate Glu-mediated depolarization of humancortical neurons268,295. More recently, it has been suggestedthat brain inflammation, cholesterol, Glu and otherneurotransmitters are interconnected in the pathology ofAD296. As these interactions become clearer, it may advanceour understanding of the molecular mechanisms andpathogenesis of AD.

Multiple sclerosis and inflammatory diseases of theCNS: Multiple sclerosis [MS] is the most common disablingneurological condition of European, North American,Australian and other temperate climates. The disease isthought to involve CNS autoantigen-directed T-lymphocytesacting in concert with a genetically determined susceptibilityand exposure to environmental induction factors297. Stillthere remains a lack of fundamental knowledge on theprimary etiology of MS and a paucity of treatments toalleviate symptoms and ultimately improve quality of life forthe patient.

The development and refinement of the inducibleanimal disease experimental autoimmune encephalomyelitis[EAE] has provided a reliable model for the study of MSoffering pathological and neurological features of strikingsimilarity to the human condition298. This model providesthe opportunity to evaluate potential new therapies for MStreatment and explore novel approaches to drug design,identify new targets, and add to the growing number of drugsin clinical trials299.

The search for compounds with the ability to modifythe onset and development of EAE has invariably focusedon immunomodulatory agents300. As elevated Gluconcentrations have been seen in MS patients29 and Gluexcitotoxicity has been used as a model of MS301, Glu and itsreceptors seem a relevant focus of research.

Over the last few years, a group of Glu-relatedcompounds have emerged, with the ability to dramaticallyimprove the course of EAE but wi thout apparentimmunosuppressive activity. These compounds have beenimplicated in the pathogenesis of neuroinflammatory diseaseby interactions with iGluRs NMDA, AMPA and Ka302–305.Hence, the discovery of NMDA and AMPA receptorinvolvement in both EAE and MS offers a plausibleassociation between the receptors, Glu, and development ofboth diseases.

As several studies have demonstrated Glu involvementin the pathology of EAE, and also MS306, the Glu antagonistamantadine has been shown to reduce the relapse rate inindividuals with MS307. Enhanced concentrations of theagonist may result from malfunctioning of activatedastrocytes normally efficient at controlling excess Gluthrough regulation of the metabolizing enzymes Gludehydrogenase and Glu synthetase. These enzymes becomedown regulated during inflammatory conditions such asEAE233,308. The alternative pathogenesis could be the lack of

a GluT produced by oligodendrocytes309,310. Regardless ofthe exact mechanism, there is an alteration of the Gluhomeostasis that does correlate with oligodendrocyte andaxonal damage311.

A mechanism via the actions of cyclooxygenase-2[COX2] and inducible nitric oxide synthase [iNOS], both ofwhich have been located in MS lesions, might account forthe increase in CNS Glu concentrations during theinflammatory phase of relapsing-remitting disease312.COX 2 -der ived p ros t ano ids , wh ich ex i s t a t h ighconcentrations in EAE and MS CNS tissues313–315, stimulateGlu release from CNS-derived cells316,317. In addition, NO,from iNOS, can increase COX2

318, plus ROS319, to react withNO to produce peroxynitrite320 that inactivates the Glutransporters321,322. These ROS directly damage myelin,oligodendrocytes, and axons323.

Understanding the mechanism of action of the Glusystem on EAE has led to develop treatment modalities forMS. Results to date have been largely negative and evidencefor a neuroprotec t ive role of Glu antagonis ts inneurodegenerative diseases is lacking275. Similarly, despiteefforts to develop compounds that act by altering themetabolism of Glu, no such drugs have been produced.

Parkinson’s disease: Parkinson’s disease [PD] isanother common and debilitating neurodegenerativedisorder, affecting 1% of the population over 65 years of age.Pathologically it is characterized by a progressive loss of thedopaminergic neurons of the substantia nigra pars compacta[SNC] and the presence of intraneuronal cytoplasmicinclusions termed Lewy bodies. The loss of these neuronscauses degeneration of the nigrostriatal tract, resulting in theclassic motor symptoms of PD, namely akinesia orbradykinesia, tremor, muscle rigidity and posturalinstability324.

Currently the treatment of PD is primarily symptomaticaiming to replace lost DA using DA replacement therapy.Whilst this approach is effective in the early stages of PD, asthe disease progresses the efficacy of the currently availabledrugs decreases and side effects are common. Furthermorethese treatments do nothing to halt the progression of thedisease. Current evidence suggests that these alteredresponses involve activation of signal transduction cascadesin striatal medium spiny neurons linking dopaminergic to coexpressed iGluRs of the NMDA and AMPA classes28.

These intraneuronal signaling pathways appear capableof modifying the phosphorylation state of NMDA andAMPA receptor subunits; resultant sensitization enhancescortical glutamatergic input, which in turn modifies striataloutput in ways that compromise motor behavior. Regulationof these spiny neuron GluR can also be affected by theactivation state of co expressed non-dopaminergicreceptors325, which sheds new insight into molecularmechanisms contributing to the integration of synaptic inputsto spiny neurons28. They also suggest novel approaches tothe pharmacotherapy of extrapyramidal motor dysfunction.Thus, current research has focused on identifying novel non-dopaminergic therapies for use in both symptomatic and


neuroprotective strategies in PD, such as LY503430326.Altered glutamatergic neurotransmission and neuronal

metabolic dysfunction are central to the pathophysiology ofPD327. The SNC is particularly exposed to oxidative stressand toxic and metabolic insults328, resulting in mitochondrialdysfunction327. Recently, the recognition that Glu that havebeen implicated in PD, particularly in the basal ganglia329,has focused research on the neuroprotective and symptom-ameliorating properties of mGluR330, G-protein-coupledGluR ligands324,329,331–333. In contrast, Group-I mGluRs(mGluR1 and 5) need to be antagonized in order to evokeprotection334 antagonists, and drugs acting on 5-HT2A, α2-adrenergic, adenosineA2A and CB1 receptors may behelpful335.

Initially, all neuroprotective mGluR ligands wereanalogues of L-Glu. Those compounds were valuable todemonstrate protection in vitro, but showed limitedapplicability in animal models, particularly in chronic tests,due to low blood-brain-barrier penetration336. Recently,systemically active and more potent and selective ligandsbecame available, e.g., the Group-II mGluR agonistsLY354740 and LY379268 or Group-I antagonists likeMPEP (mGluR5-selective) and BAY36-7620 (mGluR1-selective)334. It has now been shown that mGluR5antagonism produces strong anti-dyskinetic effects in ananimal model of PD through central inhibition of themolecular and neurochemical underpinnings of L-3,4-dihydroxyphenylalanine [L-DOPA]-induced dyskinesia337.

A wide range of antagonists of Group I and agonists ofGroup II and III mGluRs continue to be investigated in vivofollowing 6-hydroxydopamine lesioning of the nigrostriataltract in rodents125. Studies using focal drug administrationhave yielded very promising results, which have beeninconsistent in mice but show significant neuroprotectiveeffects in primates328.

A potential role for excitotoxic processes in PD hasbeen strengthened by the recent observations that thereappears to be a mitochondrially encoded defect in complex Iactivity of the electron transport chain328. An impairment ofoxidative phosphorylation enhances vulnerability toexcitotoxicity328. SNC neurons possess NMDA receptorsand there are glutamatergic inputs into the substantia nigraarea [SNA] from both the cerebral cortex and the subthalamic nucleus. As in other cases of Glu excitatorytoxicity, activation of EAA receptors results is an influx ofCa++ followed by activation of neuronal NOS, which canthen lead to the generation of peroxynitrite. Consistent withsuch a mechanism, studies of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP] neurotoxicity in both mice andprimates have shown that inhibition of neuronal NOS exertsneuroprotective effects. These results raise the prospect thatEAA antagonists for neuronal NOS inhibitors might beuseful in the treatment of PD328.

A reduced capacity to cope with metabolic demands,possibly related to impaired mitochondrial function, mightrender the SNA highly vulnerable to the effects of Glu,which acts as a neurotoxin in the presence of impaired

cellular energy metabolism. In this way, Glu may participatein the pathogenesis of PD338.

Degeneration of DA SNCs is followed by striataldopaminergic denervation, which causes a cascade offunctional modifications in the activity of basal ganglianuclei. As an excitatory neurotransmitter, Glu plays apivotal role in normal basal ganglia circuitry. Withnigrostriatal dopaminergic depletion, the glutamatergicprojections from sub thalamic nucleus to the basal gangliaoutput nuclei become overactive and there are regulatorychanges in GluRs in these regions. There is also evidence ofincreased glutamatergic activity in the striatum. In animalmodels, blockade of GluRs ameliorates the motormanifestations of PD. Therefore, it appears that abnormalpatterns of glutamatergic neurotransmission are important inthe clinical signs and symptoms of PD.

Studies using methamphetamine and MPTP reinforce alink between Glu-mediated excitotoxicity and degenerationof DA cells339. Both compounds are thought to create ametabolic stress328,339. In mesencephalic neuronal cultures,DA active cell loss produced by 3-NPA or malonate waspotentiated by NMDA and prevented by MK-801339. In vivo,striatal DA active neuronal loss produced by intranigralinfusions of malonate was also potentiated by intranigralNMDA and prevented by systemic MK-801, supporting thehypothesis of NMDA receptor involvement in degenerationof dopamine active neurons. This effect is likely to occur inthe SNA rather than in the striatum339.

6. Other neurological conditionsCerebral ischemia (stroke) and traumatic brain injury:

Stroke and neurotrauma mediate neuronal death through aseries of events that involve multiple interdependentmolecular pathways. It has been suggested hypoxia triggersthese pathways following elevations in extracellular EAAs,primarily Glu340. Increased activation of iGluR also hasbeen implicated in the pathophysiology of traumaticbrain340–344 and spinal cord injuries345,346. In addition,mGluRs participate broadly in the regulation of Gluneurotransmission48, yet their role in post-traumatic CNSinjury has been largely unexplored.

There has been limited research to address a possiblerole for mGluR in modulating neuronal death after variousnon-traumatic insults. To a certain extent, Groups I and IImGluR have contrasting actions. Group I receptors(mGluR1,5) may potentiate neuronal excitation andexcitotoxicity14,347,348, possibly through positive modulationof NMDA receptor activity349.

Group II receptors (mGluR2/3) may exert a protectiveeffect347,350 possibly through presynaptic inhibition of Glurelease14,351,352. Because of these apparently opposingactions, and the fact that more discriminating agonists andantagonists are not yet available, it is not surprising that datahave been less than conclusive with regard to the role ofmGluR in neuronal death. Indeed, the cyclic Glu analog,1S,1R-1-aminocyclopentane-1,3-dicarboxylic acid [1S,1R-ACPD], which is an agonist at both Group I and Group II

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receptor sites contributes to or protects against celldeath204,205,352–356.

It appears as though neuroprotection by glial mGluRare mediated by transforming growth factor β [TGFβ]212.The synthesis of phenylglycine derivatives has permitteddifferentiation of the activity of various mGluR groupsthrough comparison of the ac t iv i t ies of se lectedcompounds351. However, differentiation of receptorsubtypes within these groups has remained problematic17.

NMDA and AMPA receptor antagonists have beenshown to be powerful neuroprotective agents in animalmodels of stroke203. However, NMDA receptor mediatedexcitotoxicity can contribute to cerebral hypoxia toischemia357. In permanent or reversible occlusion of themiddle cerebral arteries, these antagonists consistentlyreduce the volume of cortex that is infarcted for 24 h for oneor more weeks later. Interestingly, they do not protect thestriatum following ischemia358,359. However, it is possiblethat AMPA receptor antagonists reduce cortical and whitematter damage in vitro and in vivo360.

Spinal cord injury often damages the axons of cord-projecting central neurons361, and initiates a cascade ofbiochemical events that lead to an increase in theextracellular Glu concentrations362. Rat rubrospinal neuronshave been used as a model to examine their excitatory inputfollowing upper cervical axotomy. Anterograde tracingshows that the primary afferents from the cerebellumterminated in a pattern similar to that of control animals.Ultrastructurally, neurons in the injured nucleus arecontacted by excitatory synapses of normal appearance, withno sign of glial stripping. Since cerebellar fibers areglutamatergic, the expression of iGluR subunits GluR1-4 andNR1 have been examined for AMPA and NMDA receptorsin control and injured neurons using immunolabelingmethods361. In control neurons, GluR2 appears to be lowcompared with GluR1, GluR3, and GluR4, while NR1labeling was intense.

Following unilateral tractotomy, the levels ofexpression of each subunit in axotomized neurons appearsnormal, with the exception that they are lower than those ofcontrol neurons of the non-lesioned side at 2–6 days postinjury. These findings suggest that axotomized neurons areonly temporarily protected from excitotoxicity361. This is insharp contrast to the responses of central neurons thatinnervate peripheral targets, in which both synaptic strippingand reduction of their iGluR subunits persist followingaxotomy361.

The absence of an injury-induced trimming of afferentsand stripping of synapses and the lack of a persistent downregulation of postsynaptic receptors might enable injuredcord-projection neurons to continue to control theirsupraspinal targets during most of their post injury survival.Although these events may support neurons by providingtrophic influences, it nevertheless may subject them toexcitotoxicity and ultimately lead to their degenerativefate344,363.

The neuroprotection of the Glu system is greatest if the

antagonist, such as an AMPA antagonist364 is given close tothe time of onset of the ischemia, as efficacy is diminishedwith delay, and protection usually disappears with drugadministration at 90–120 min post-arterial occlusion. It hasbeen suggested that targeting the AMPA receptor unit GluR2would be a useful strategy for stroke therapy364, althoughother authors are less impressed with efficacy of novelNMDA antagonists363. Whereas most AMPA type Gluchannels are Ca++ impermeable, an evolving body ofevidence supports the contention that relatively unusual Ca++

permeable AMPA channels might be crucial contributors toinjury in these conditions. These channels are preferentiallyexpressed in discrete neuronal subpopulations, and theirnumbers appear to be up regulated in ALS and stroke. Inaddition, unlike NMDA channels, Ca++ permeable AMPAchannels are not blocked by Mg++, but are highly permeableto another potentially harmful endogenous cation, zinc[Zn++]; hence, targeting these channels might provide newavenues in the treatment of some neurological diseases363,364.

Administration of the AIDA (Group I mGluRantagonist), LY 367385 (mGluR specific antagonist), orMPEP (mGluR5 specific antagonist) in rats following injuryat T10 showed that AIDA and LY 367385-treated animalshad improved locomotor scores, and LY 367385 potentiatedthe development of thermal hyperalgesia362. MPEP had noeffect on locomotor recovery or mechanical allodynia, butattenuated the development of thermal hyperalgesia. AIDAand LY 367385 treatment resulted in a significant increase intissue sparing at four weeks following injury compared withthe vehicle treated control group362.

These nonclinical data, and similar data for rodentmodels of traumatic brain injury, have led to major clinicaltrials of NMDA receptor antagonists in stroke and in headinjury363. Unfortunately, few of the trials have showntherapeutic benefit as the adverse effects have far exceededthe therapeutic benefits. Adverse events involved cardiacarrhythmias, hypotension, hypertension and cognitive sideeffects. AMPA antagonists that were shown to be effectivein animal models initially have proved unsuitable for clinicaltrial, but several compounds under development are likely togo forward to clinical trial in the near future.

Glu plays an important role in reperfusion injuryfollowing ischemia. Glu excitotoxicity, oxidative stress, andacidosis are primary mediators of neuronal death duringischemia and reperfusion344. Astrocytes influence theseprocesses in several ways. Glu uptake by astrocytesnormally prevents excitotoxic Glu elevations in brainextracellular space, and this process appears to be a criticaldeterminant of neuronal survival in the ischemicpenumbra365. Conversely, Glu efflux from astrocytes byreversal of Glu uptake, volume sensitive organic ionchannels, and other routes may contribute to extracellularGlu elevations.

Gly and D-serine, both of which are transported byastrocytes, modulate Glu activation of neuronal NMDAreceptors. D-serine production is localized exclusively toastrocytes365. Astrocytes influence neuronal antioxidant


status through release of ascorbate and uptake of its oxidizedform, dehydroascorbate, and by indirectly supportingneuronal glutathione metabolism. In addition, glutathione inastrocytes can serve as a sink for NO and thereby reduceneuronal oxidant stress during ischemia365.

Astrocytes probably also influence neuronal survival inthe post-ischemic period. Reactive astrocytes secrete NO,tumor necrosis factor α [TNFα], matrix metalloproteinases,and other factors that can contribute to delayed neuronaldeath, and facilitate brain edema via aquaporin-4 channelslocalized to the astrocyte end foot-endothelial interface. Onthe other hand erythropoietin [EPO], a paracrine messengerin brain, is produced by astrocytes and up regulated afterischemia. Erythropoietin stimulates the JAK2 and nuclearfactor-κβ [NF-κβ] signaling pathways in neurons to preventprogrammed cell death after ischemic or excitotoxic stress.Astrocytes also secrete several angiogenic and neurotrophicfactors that are important for vascular and neuronalregeneration after stroke365,366.

E p i l e p s y : C o m p e l l i n g n e u r o p h y s i o l o g i c ,pharmacologic, biochemical and anatomical evidence hasbeen accumulated over the last several decades firmlyimplicating the NMDA and AMPA/Ka iGluR and mGluR-mediated mechanisms in epileptic seizures367–369. Excitatoryglutamatergic mechanisms are involved during both acute,transient, evoked seizures and long-term, adaptive cellularplasticity associated with epileptogenesis in chronic epilepsymodels such as amygdala-kindled rats or rats withspontaneous, recurring seizures after an early episode ofinduced status epilepticus370.

Recently, seizure activity has been shown to changeGlu and GluR distribution371, in particular mGluRs372. Thus,epilepsy would seem an excellent target on which Glu mayexcite foci of neurons to produce seizure activity via iGluRand mGluR373. Therefore it is not surprising to note thatNMDA and AMPA receptor antagonists are powerfulanticonvulsants in a wide range of animal models ofepilepsy374. These antagonists decrease the concentration ofmGluRs375, and, therefore, the use of GluRs in modulation ofepilepsy should be theoretically possible.

Pure NMDA or AMPA receptor antagonists have yet tohave much clinical history, although several agents thatshow such properties mixed with other actions have beenintroduced e.g., felbamate (NMDA antagonism) andtopiramate, (AMPA antagonism), or are under trial e.g.,remacemide, (NMDA antagonism). Antagonists at Group Iand agonists at Group III mGluRs also appear to be potentialcandidates for clinical trial in epilepsy369,376,377. Regardlessof the progress, GluR still remains a strategic target for thetreatment of epilepsy378,379.

Our understanding of the molecular basis of epilepsy isstill limited. Genetically, a number of mutations underlyingnaturally occurring epileptic syndromes have been identifiedin animals and humans. These mutations mainly involveion-channel defects, which include voltage-sensitive Ca++,K+ or Na+ channels, Na+-hydrogen exchangers and nicotiniccholinergic receptors380,381. It is questionable as to whether

mutations directly involving glutamatergic transmittersystem components (Glu, iGluR, mGluR, and GluT) arepresent374.

Epilepsy investigators have theorized that a dysfunctionin glial cells, and not in neurons or synapses, may be theinitiating cause of epilepsy382. This suggestion has beenbased on several observations where robust reactive gliosisis necessary to induce posttraumatic epilepsy383.

Astrocytes play a crucial role in ion homeostasis and,therefore, in neuronal excitability384. Manipulation of glialcell volume and, thus, of extracellular volume affectsneuronal hyper synchronicity, indicating that the cell surfaceand possible the cytoplasm are needed for hypersynchronicity385,386. Astrocytes have a direct role in ther e g u l a t i o n o f s y n a p t i c s t r e n g t h a n d n e u r o n a lexcitability387,388. Thus, evidence has been steadilyaccumulating that a dysfunction in the astrocyticcompartment can lower seizure threshold and precipitateseizures382.

Regardless of the site of initiation, seizures can beprovoked in epileptic and non-epileptic animals and humansby a wide number of glutamatergic molecular mechanisms.Despite the varied primary pathology in epileptic seizures,the mechanisms involved in generating and spreadingepileptic discharges converge on a common cellularpathology in which the excitatory glutamatergic systemplays a key role.

Psychiatric disturbances: It is recognized that the acutesigns of PCP intoxication are reversed in the rat by the GroupII mGluR agonist LY 354740389. It is also suggested thatstandard antipsychotic drugs such as haloperidol andclozapine may be effective partially through NMDAreceptor potentiation390. Similarly, a Gly site NMDAantagonist, L-701324, has a neuroleptic-like action inseveral animal models of psychosis391.

Schizophrenia: Impairments in certain cognitivefunctions mediated by the dorsolateral prefrontal cortex,such as working memory, are core features of schizophrenia.These cognitive functions in schizophrenia have beenassociated with a pronounced reduction of total neuronnumber in mediodorsal thalamic nucleus and nucleusaccumbens392. Several neurochemical hypotheses have beenproposed to account for the origin and symptoms ofschizophrenia, including abnormal dopaminergic,GABAergic, and glutamatergic neurotransmission393–399.

Pharmacological studies showing that NMDA receptorantagonists, modulated by mGluR1 and mGluR5 such as PCPand ketamine might play a role in schizophrenia400, as manyof the psychotic signs and symptoms of schizophrenia can beseen normal exposed to these drugs399,401–404. A dysregulatedglutamatergic state in schizophrenia has been characterizedby abnormal glutamatergic neurotransmission in thehippocampus, entorhinal cingulate, and prefrontalcortices394,405–409 involving the glutamatergic system inlearning, memory, emotion, and behavior398,410,411.

Abnormal GABAerg ic neuro t ransmiss ion inschizophrenia includes lower GABA uptake and release in the

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frontal cortex412–414, lower glutamic acid decarboxylaseactivities and mRNA in some brain regions and neurons415–417,greater [3H]-muscimol and GABAA receptor binding418,419,fewer small, putatively GABAergic neurons in thehippocampus and the anterior cingulate cortex420–422, and lessGABA transporter protein1 [GABATP1] in axon terminals ofchandelier neurons423. Thus, in addition to glutamatergicdysfunction in schizophrenia, there are concurrent defects inGABAergic neurotransmission414,419,424.

Hypofunction of the NMDA-receptor also maycontribute to the pathophysiology of schizophrenia425.Clinical studies using the NMDA and Gly-site agonists Glyand D-serine426 indicate significant improvements innegative and cognitive symptoms of schizophrenia.Therefore, reduced activation of the Gly binding site of theNMDA receptor probably contributes substantially to theongoing clinical signs and symptoms. Since Gly is notactively transported across the blood brain barrier, plasmalevels of this compound are in equilibrium with brainlevels427,428,429.

Elevated levels of homocysteine [HC], which acts inpart as an NMDA-Gly site antagonist430, may also contributeto symptom development in schizophrenia as high HCplasma leve l s a re an es tab l i shed r i sk fac to r fo rcardiovascular, cerebrovascular, and Alzheimer’s diseaseand have been observed in schizophrenia431. It has beensuggested that the management of clinical symptoms ofschizophrenia might be assisted by the administration of folicacid, pyridoxine, and B12, which help reduce HC levels432.

Structural and functional pathology have been detectedin the thalamus in patients suffering from schizophrenia444.Lower thalamic cell numbers and volume are not as a reliableindicator of schizophrenia in comparison to decreasedthalamic metabolism433–443 because most thalamic afferentsand efferents are use Glu as a neurotransmitter444–446 andpharmacological evidence implicates glutamatergicdysfunction in schizophrenia.

NMDA, AMPA, Ka iGluRs along with mGluRs makeup the four families of GluRs that are expressed in thethalamus13,447, and NMDA receptor abnormalities are mostoften associated with schizophrenia401–404,448,449. Adjuncttreatment with conventional antipsychotics of agonists andpartial agonists of the Gly coagonist site of the NMDAreceptor has been reported in some studies to amelioratenegative psychotic symptoms450–455.

NMDA receptor hypoactivity is associated withschizophrenia either due to primary defects in NMDAreceptors or from dysfunction of a GluR family456–463, andsecondarily affects activation of AMPA receptors.Interestingly, AMPA receptors are extensively co localizedwith NMDA receptors at glutamatergic terminals464. Inaddition, pre- and postsynaptic mGluRs affect NMDAreceptor-mediated neurotransmission389,465,466, a dysfunctionof which could mimic abnormal NMDA receptor activity467.

A recent focus of schizophrenia research is thedisruption of white-matter integrity468. This research usingmagnetic transfer imaging and diffusion tensor imaging,

which showed differences in white-matter integrity and tractcoherence in persons with schizophrenia compared tocontrols469. Oligodendrocytes, in particular, have been thesubject of increased study after gene microarray analysesrevealed that six myelin-related genes specific tooligodendrocytes have decreased expression levels inschizophrenia. These cells have also been shown to bedecreased in number in the superior frontal gyrus of subjectswith schizophrenia468.

Stress-related conditions: Stress-related psychiatricdisorders, such as depression and anxiety disorders, areprevalent and are of enormous public health concern470. Thehypothalamic-pituitary-adrenal [HPA] axis is the keyregulator of the stress reaction in the fetus, child andadult471. Dysregulation of this axis has been shown to play acentral role in the pathophysiology of anxiety anddepressive disorders472–478, providing evidence that theglutamatergic system, and in particular mGluRs, play acritical role in the pathophysiology of stress-relatedbehavioural disorders479–482. In fact, Group-III mGluRsubtypes (including mGluR4,6-8) have been implicated inanxiety and depression483–488.

(1) Depression: There is now doubt that Glu plays a rolein depression and antidepressant activity. In fact, a singleintravenous dose of an NMDA receptor antagonist issufficient to produce sustained relief from depressivesymptoms480. NMDA receptor antagonists, Group I mGluRs(mGluR1 and mGluR5) antagonists, and positive modulatorsof AMPA receptors have antidepressant-like activity in avariety of nonclinical models489, which may be initiated byGlu interaction with NOS490,491.

There is extensive colocalization of EAA andmonoamine markers in nuclei such as the locus coeruleusand dorsal raphe, which are central to depression; therefore itis likely that regulation of monoaminergic and EAAneurotransmission and ant idepressant effects areinterdependent489. Certainly, there is evidence implicatingdisturbances in Glu metabolism, NMDA, and mGluR1,5receptors in depression and suicidal tendencies480.

(2) Anxiety: Anxiety disorders include panic disorder,post-traumatic stress disorder [PTSD], obsessive compulsivedisorder [OCD], specific phobias, and others492. Nonclinicalstudies have shown that the amygdala plays a key role in fearcircuitry, so it is not surprising that abnormalities inamygdala pathways can affect the acquisition and expressionof fear conditioning. Drugs such as NMDA antagonists, andblockers of voltage-gated Ca++ channels in the amygdala,may block these effects493,494.

Amnesia: Memory loss is characteristic of Gluexcitotoxicity as seen in DMA poisoning, so targeting Glu’saction at AMPA receptors may be useful in addressingamnesia. D-cycloserine, a partial agonist at the Gly site ofthe NMDA receptor , has been shown to enhanceperformance in various animal memory tasks32, In additionto demonstrating memory enhancement in animal models495,elderly humans are also benefited496.

Pain: In addition to NE effects, hyperalgesia clearly


involves NMDA receptors in the spinal cord, and peripheralmGluRs a re thought to media te a component o fhyperalgesia497,498. It is for this reason that GluR5-selectiveantagonists such as LY 294,486 appear to be analgesic499.

HIV - AIDS: Many individuals with acquiredimmunodeficiency syndrome [AIDS] eventually suffer fromneurological disease, including dysfunction of cognition,movement, and sensation500, all characterized by neuronalinjury and loss501, even in the absence of neuronal infectionwith human immunodeficiency virus type 1 [HIV-1]503.

HIV-1, or immune-related, toxins lead indirectly to theinjury or death of neurons via a potentially complex web ofinteractions among microglia, astrocytes, and neurons502.Astrocytes seem to manage the interaction of HIV-infectedmacrophages, microglia, or monocytes, resulting in asecretion of substances that potentially contribute toneurotoxicity, such as eicosanoids and HIV-1 envelopeprotein gp120503. Regardless of the mechanism of a action,it still is the critical influx of Ca++ that kills the neurons.

These secreted substances lead to increased Glu releaseor decreased Glu reuptake; hence, free Glu becomes moreabundant. Macrophages also induce the release of the Glu-like agonist quinolinate. The stimulation of γ-interferon[IFN-γ], cytokines, (including TNFα) and interleukin-1 β[IL-1β] production and release by macrophages contributesto astrogliosis500,502,503.

7. Special sensesGlu effects in the special senses are mostly confined to

the neurological components of each special sense504.Eye: Loss of retinal ganglion cells [RGCs] is a hallmark

of many ophthalmic diseases including glaucoma, diabetesretinopathy, retinal ischemia due to central artery occlusion,anterior ischemic optic neuropathy and may be significant inoptic neuritis, optic nerve trauma, and AIDS505.

The re t ina conta ins a d ivers i ty of GluR andGluTs200,506–511, each localized to different types of cells andmediating different functions in the processing of visualsignals512,513. In fact, the expression of GluR genes hasdefined the localization of GluR1 through GluR7 mRNAs inthe mammalian retina514. The retina is composed of sevencell types, which are organized into layers, with nuclearlayers containing somata separated by plexiform layers filledwith processes. Absorption of light initiating the signaltransduction cascade through the retina is done at the level ofthe most distal cells—photoreceptors515. Photoreceptors arepresynaptic to horizontal and bipolar cell dendritic processesin the outer plexiform layer [OPL]516.

Bipolar cells relay the signal to the inner retina, wherethey are presynaptic to amacrine and ganglion cells in theinner plexiform layer [IPL]. These amacrine cells containAMPA-, NMDA-, GABA-, and Gly activated currents517–521

and they are important in the regulation of mGluR522,523.Ganglion cell axons form the optic nerve and transmit thesignal to the brain. It is the connections betweenphotoreceptor, bipolar, and ganglion cells that form thevertical transduction pathway through the retina516.

Glu is the neurotransmitter released between elementsin this pathway and can be toxic524 in certain conditions, asdescribed below. The pathway is modulated in the OPLthrough electrical525 and GABAergic synapses arising fromneighboring horizontal cells526. Both synaptic layers of theretina contain Group I mGluR: mGluR1α and mGluR5α

527.Glycinergic and dopaminergic interplexiform cells alsoprovide inputs to the OPL528,529, whereas in the IPL,inhibitory GABAergic and glycinergic inputs from amacrinecells modify bipolar-to-ganglion cell signaling516. Inaddition to neurons, Muller glial cells are also present.Muller cells, which are the radial glial cells of the retina,extend the width of the retina and play a role in the removalof excess Glu530.

Neuronal activity appears paradoxical in the retina, butGlu is believed to be the major excitatory neurotransmitter atthis site. Neurons characterized by their response to light,with ON-type cells depolarizing in response to a lightstimulus and OFF-cells hyperpolarizing to light ordepolarizing in the dark. Signal transduction to both ON andOFF pathways is initiated by photoreceptors, which releaseGlu in the absence of a stimulus, i.e., the dark, depolarizingOFF-cells and hyperpolarizing ON-cells22. High levels ofthe Group II mGluR are expressed in these cells531,532. Infact, the separation between ON- and OFF-pathways expressdifferent types of postsynaptic GluRs, pathways that are alsomorphologically distinct with the processes of OFF-amacrine, ganglion, and bipolar cells533–537.

As discussed earlier, Glu can be toxic in the eye inelevated concentrations524 probably through excitotoxicactivity538 as can be seen with excess Gly539. GluRs areimportant to the expression of the excitotoxic effects of Gluand Gly, although retinal ganglion cells do not appear to beas sensitive to excitotoxicity as are other neural cells in theeye540.

Neuroactive Glu is stored in synaptic vesicles inpresynaptic axon terminals541 and is incorporated into thevesicles by a Na+-independent, ATP-dependent GluTlocated in the vesicular membrane541–543. GluTs maintain theconcentration of Glu within the synaptic cleft at low levels,preventing Glu-induced cell death544–547. Glial Glu rapidlybreaks down into glutamine530, which is then exported andincorporated into surrounding neurons548. Neurons can thenlater synthesize Glu from this glutamine548,549.

Neuronal Glu activity is not the only method of Glucycling and concentration management. Oligodendrocytesare important and act as a negative regulatory activity, butare harmed by excessive Glu149. It is interesting to note thatGluR activity is necessary for normal development of tectalcells550,551, probably through NMDA types of GluR552.

Retinal photoreceptors, bipolar cells, and ganglion cellsare can be visualized microscopically as they are Gluimmunoreactive68,71,553–559. and surrounding cells can alsodisplay weak labeling with Glu antibodies553,554,558–560.However, neurons are believed to release GABA, not Glu, astheir neurotransmitter561, suggesting the weak Glu labelingreflects the pool of metabolic Glu used in the synthesis of

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GABA558,560. Finally, GluRs are important in the visualcortex, where mGluRs have been shown to be important inprocessing of visual information in the superior colliculus562.

(1) Ischemia: Glu is an important component to thepathogenesis and pathology of ocular ischemia563, morespecifically there is a decrease in Glu-Asp transporter[GLAST] in ocular ischemia564. The GluR subtypesinvolved in organ specific ischemic responses variesdepending on the tissue, e.g., in hippocampal neurons asubunit-specific down regulation of GluR2 precedes theactual neurodegeneration, whereas the retina does not565.Retinal ischemia and reperfusion changes the quantitativeexpression of the different AMPA-type GluR subunits566,affecting excitatory synaptic transmission in the innerretina227. In fact, excitotoxic mechanisms are involved inischemia-induced neuronal death in the retina, and ROSgenerated under conditions of ischemia may be a primarycause of retinal damage567. A number of GluR antagonistshave been used experimentally to show that some do protectagainst ischemia-induced damage568. Ischemia-inducedaxonal loss in large retinal ganglion cell axons is similar tothat seen in glaucoma569.

(2) Glaucoma: Although raised intraocular pressure[IOP] is a significant risk factor for developing glaucoma,there is no set threshold for IOP that causes glaucoma. Oneperson may develop nerve damage at a relatively lowpressure, while another person may have high IOP for yearsand yet never develop damage. Untreated glaucoma shows acharacteristic pattern of optic neuropathy leading topermanent damage of the optic nerve and resultant visualfield loss, which can progress to blindness570,571.

Increased IOP has been shown to increase Glu in theoptic nerve572, which may implicate Glu and GluRs in thedevelopment of glaucoma. However, retinal ischemia ismore central to the understanding of the pathogenesis ofglaucoma, hence neuroprotection in the face of ischemiawould be of great assistance in the clinical treatment of thedisease. It is for this reason that management of glaucoma isdirected at the control of IOP, with therapy preventing thedeath of ganglion cells as the main goal of treatment.

Not all types of retinal ischemia lead to the pathologicfindings seen in glaucomatous retinas or to cupping in theoptic disk area573. It appears as though EAA transporterEAAT-1 is down regulated resulting in the elevated Glulevels that exist in the vitreous humor of patients withglaucoma574. For this reason, compounds that block NMDAreceptors to prevent the action of the released Glu orsubstances that interfere with the subsequent cycle of eventsthat lead to cell death via influx of Ca++ and the generation ofROS have been shown to be neuroprotective567 e.g.,betaxolol573.

(3) Diabetic retinopathy: Diabetic retinopathy is aserious consequence of diabetes mellitus. Diabeticretinopathy is a major cause of disability with an estimated40% of adults over the age of 40 years having some form ofdiabetic retinopathy and 8% having vision-impairingdiabetic retinopathy575. Recent work suggests that elevated

glucose may alter Glu neurotransmission and Ca++

homeostasis in the retina, which may have implications forthe mechanisms of vision loss in diabetic retinopathy576.GluRs have been shown to affect altered synaptictransmission in the IPL and OPL in the diabetic retina577, andare implicated in ocular Glu toxicity578.

Recently, the receptors involved in this alteration havebeen identified as AMPA GluR channels576. Using primaryretinal cell cultures, high glucose was shown to significantlydecreased the protein content of GluR1 and GluR6,7 subunitsand increased the protein content of GluR2 and Ka2 subunits.It also decreased Ca++ permeability through AMPA receptor-associated channels. Hence elevated glucose altersneurotransmission via alteration of Glu homeostasis inaddition to ischemia resulting from the later stages of thedisease.

Ear: Evidence has accumulated over the yearssupporting Glu as the primary neurotransmitter used by haircells in afferent cochlear neurotransmission579. GluRs areinvolved in excitatory neurotransmission at the first auditorysynapse between the inner hair cells and the spiral ganglion[SG] neurons. Fast synaptic transmission in the cochlea ismainly mediated by desensitizing AMPA receptors580 andGroup I mGluR (mGluR1,5)581, which are slower in theirexcitation were pharmacological specificity and quicklydesensitized.

In the cochlea, excitotoxicity may occur in twopathological conditions: anoxia and noise trauma582. Thelesions are characterized by a two-step mechanism. Firstly,an acute swelling, which primarily depends on the AMPAand Ka type of receptors, together with a disruption of type Iafferent dendrites, which are postsynaptic structures,resulting in a loss of function. Within the next five days,synaptic repair may be observed with a full or a partialrecovery of cochlear potentials. The second phase ofexcitotoxicity, which may develop after strong or repetitiveinjury, consists of a cascade of metabolic events triggered bythe entry of Ca++, which leads to neuronal death in the SG583.

Ongoing experiments in animals, tracking themolecular basis of both these processes, preempt thedevelopment of new strategies to help neurites to regrow andreconnect properly, and to prevent or delay neuronal death inthe SG. Human applications should follow, and a local transtympanic strategy against cochlear excitotoxicity may, in thenear future, prove to be helpful in ischemic- or noise-inducedsudden deafness, as well as the related tinnitus584.

Inhibiting mGluRs in the cochlea does not significantlyaffect the hearing threshold. In contrast, blocking mGluRslowers the amplitude of compound action potentials atlouder sound levels and reduced the noise-inducedtemporary threshold shift, indicating that the cochlea is moreresistant to noise-induced temporary hearing losses withoutthe activation of metabotropic glutamate receptor inhibitors[mGluRIs] in SG neurons581,585–587. The expression ofsynaptic NMDA receptors in the auditory cortex is dynamicand is bidirectionally regulated by auditory activity588.Interestingly, GABA is also active at this site. Here the


GABAergic component of the olivocochlear systemcontributes to the long-term maintenance of hair cells andneurons in the inner ear589,590.

Disease entities relating to ear function that have beeninvestigated include vomiting, vertigo and tinnitus.Vomiting and vertigo are dependant on AMPA and NMDAGluRs. Antagonism to GluR stimulation has a dampingeffect of GABA591. Salicylate, the active component ofaspirin, is known to induce tinnitus. However, the site andthe mechanism of generation of tinnitus induced bysalicylate remain unclear, but it is thought that salicylateinduces tinnitus through activation of cochlear NMDAreceptors592.

8. EndocrineGluRs have been identified in endocrine tissues

including the endocrine pancreas, pituitary, pineal gland, andadrenal gland44,64,73,77,79,84,85,593–597. The identification ofthese GluR has not yet been translated into their response todisease states. Probably the most hopeful use of GluRs indisease lies in their role in pancreatic function and diabetesmellitus.

Pancreas: Diabetes mellitus, an endocrine disorder of

Table 1. Ionototropic GluR Expression in Retinal Neurons and Retinal Retinal cell type or layer Non-NMDA receptor subunits

PhotoreceptorsGluR6/7 (single cone outer segments)GluR1 (cone pedicles)

Outer plexiform layerGluR2, GluR2/3, GluR6/7

GluR2, GluR2/3 (photoreceptors)

Bipolar cells

GluR2 (Mb cells)GluR2, GluR2/3

GluR2 and/or GluR4GluR2 (RBC)

Horizontal cellsGluR6/7GluR2/3

Inner nuclear layer

GluR2/3, GluR6/7

GluR1, 2, 5 > GluR4 (outer third), GluR1,2, 5 (middle third), GluR1-5 (inner third)GluR1-7KA2 (homogenous), GluR6 (inner),GluR7 (inner two thirds)

Inner plexiform layerGluR1, GluR2/3, GluR6/7

Amacrine cellsGluR6GluR2/3GluR1, GluR2/3

Ganglion cells and ganglioncells layer

GluR1GluR2/3, GluR6/7GluR1-5GluR1-7GluR6-7, KA2

Muller cells GluR4

carbohydrate metabolism resulting primarily frominadequate insulin release induces cognitive impairment anddefects of LTP in the hippocampus, considered to be animportant mechanism of learning and memory in mammals.As previously discussed, LTP is known to require regulationof the GluR properties. According to many studies, defectsof long-term potentiation in the hippocampus of diabeticanimals are due to abnormal GluRs598. For this reason it ispossible that deficits in long-term potentiation duringchronic diabetes might arise from dysfunction of the NMDAsubtype of GluRs in early stages of the disease.

Investigation into the differential distribution of theGluR subunits in the pancreas showed that GluR1 and GluR4were mainly localized to insulin-secreting cells in the centralmass of the pancreatic islet, whereas GluR2/ 3 waspreferentially localized in the peripheral rim composed ofnon-insulin-secreting islet cells84–86,593,599,600. It appears thatinsulin- and non-insulin-secreting cells express differentAMPA receptor subunits, which may be used to mediatetheir hormone secretion77,78,601.

AMPA receptors are located in the α,β and pancreaticparenchyma [PP] cells, but are generally absent from the γcells, whereas Ka receptors were expressed in the α and γ

Layers Visualized by Immunohistochemistry and In Situ HybridizationNMDA receptor subunits Species (ref)

Goldfish696

Cat511

Rat696

NR2A (punctate) Cat697

Goldfish696

Goldfish696

Rat696

NR2D (RBC) Rat698

NR1 (RBC) Rat700

Rat699

Goldfish696

Cat511

Rat696

NR2A (inner) Rat697

Rat699

Rat, Cat514

NR1 (homogenous), NR2A-B (innerthird, patchy), NR2C (inner two-thirds) Rat517

Rat696

NR2A Rat, cat, rabbit, monkey697

NR2A-C Rat517

Cat511

Rat696

Rat696

Rat696

Rat699

Rat, Cat514

NR1, NR2A-C Rat517

Rat696

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cells although they were not found in β or PP cells86. Inaddition, localization and function of Group III mGluR havebeen investigated and mGluR8 has been recognized onglucagon-secreting cells602. These observations add to theevidence that these receptors may be involved in theregulation of hormone secretion74,76–78,593 and hence could beimportant in diabetes mellitus.

Elevated Glu has been shown to depolarize islet cells86.Intracellular Ca++ measurements and electrophysiologicalrecordings showed that Ka, AMPA and NMDA elicitincreases in Ca++ in single β-pancreatic cells and depolarizedthem. In addition, Ka and AMPA stimulated the release ofinsulin whereas NMDA did not13. This stimulatory effectwas dependent on the glucose concentration. In thisexperiment Glu stimulated insulin release in the presence ofan elevated glucose concentration but not in the presence ofa low concentration. Hence, Glu is a potentiator of glucose-induced insulin release102. mGluRs have also been identifiedin pancreatic islet cells and as mGlu8 receptors have beenseen in glucagon secreting cells and intrapancreatic neurons,they may play a role in glucagons secretion602.

In addition to the GluRs, the presence of GABAreceptors has also been reported in the PP cells74,134,603.Therefore, as with cells of the CNS, the balance in theactivities of both GluR and GABA receptors probablydetermines the final effect on these cells.

Pituitary: Although GluRs have been described in thepituitary, the neurohypophysis possesses a two-fold higherbinding activity than that found in the adenohypophysis595,the role of Glu, GluR and Glu transporters in pituitarydisease is not clear, but they are important in modulation ofthe HPA604. mGluR2/3 have a central role in modeling theanterior pituitary via induction of apoptosis605.

mGluR2/3 is not the only receptor to be described in thehypophysis. In addition to mGluR2/3, antibodies that arespecific to GluR1 and GluR4 can be visualized in each lobe ofthe pituitary gland. Here, GluR1- and GluR2/3-positive cellscan be identified in the anterior and intermediate lobe, andintense terminals of GluR4 and weak terminals of GluR2/3were observed in the posterior lobe. The immunoreactivityappears to be at the axonal terminal of the neurosecretorymagnocellular cells, suggesting that Glu might have animportant role in regulation of the anterior pituitary73. Morerecently, GluR6/7 subunits of Ka receptor showed upregulation in response to the systemic administration of aGlu agonis606, but MSG does not elicit a similar response607.How these receptors are expressed in such diseases asCushing’s syndrome and have yet to be investigated.

Some work has centered on release of varioushormones and growth factors from the pituitary. Gluagonists, including AMPA, Ka, NMDA, and Glu elicit aluteinizing hormone releasing hormone [LHRH] release invitro and the response is greatest for AMPA, which suggeststhat non-NMDA receptors are primarily involved in Glu-induced LHRH release106,608. Indeed, mGluR activationstimulated the release of vasopressin [VP] and oxytocin[OT]609; however, the relationship of GluRs to reproductive

health still needs to be elucidated fully.Detailed characterization of the effects of agonists and

antagonists of GluRs on growth hormone [GH] releaserevealed that activation of NMDA, Ka and AMPA receptorsat different age-points resulted in clear-cut stimulation of GHsecretion, although age- and sex-dependent differences weredetected in the pattern of response to the different agonists610.This stimulatory action was proven NO-dependent and notexerted at the pituitary level. In addition, evaluation of therole of hypothalamic growth hormone-releasing hormone[GHRH] in the stimulatory action of NMDA by means ofimmunoneutralization of endogenous GHRH or destructionof GHRH producing neurons suggested the involvement ofsignals other than GHRH in this response. Similarly, it hasbeen shown that immortalized gonadotrophin releasinghormone [GnRH] neurons (GT1 cells) express GluRs whengrown in culture and show enhanced GnRH secretion inresponse to GluR agonists611,612. Interpretation of thesefindings with respect to disease of growth and reproductioncan only be made when further research results have beenpublished.

Adrenals: There is a dearth of literature regarding therole of GluRs in diseases affecting the adrenal medulla andcortex. GluR1 is found in the zona glomerulosa [ZG] of thecortex, GluR3 in the remaining parts of the cortex, GluR2 inadrenal medullary cells and GluR4 at a very low level in theZG. All four GluR mRNAs are found in medullary ganglioncells where the flip form of GluR2 and GluR3 dominate andthe GluR2 mRNA is present in the arginine encoding form613.Different cell populations of the adrenal gland may expresshomomeric forms of different receptor subtypes614.

Pineal: Glu inhibi ts NE-dependent melatoninsynthesis615. Consistent with this observation, specifica g o n i s t s o f m G l u R 2 / 3 , i n c l u d i n g 1 - ( 1S , 3 R ) -aminocyclopentane-1,3-dicarboxylic acid [tACPD], inhibitNE-dependent melatonin synthesis, whereas agonists forother types of GluRs do not615. iGluRs have been shown totrigger microvesicle-mediated exocytosis of Glu from pinealcells616, which might serve as a feedback circuit for theabove. The significance of these findings with respect topineal function is not clear; however, one could postulatethat Glu might be involved in effecting “jet lag”.

9. Immune systemSeveral mGluRs, mGluR1-3,5, have been reported in the

thymic stromal cell line [TC1S] and in thymocytes. TC1Sexpresses mGluR2/3&5, whereas thymocytes expressmGluR1,3&5. The amount of each mGluR in unsortedthymocytes varies in relationship to one another: 70%expressed mGluR5, 50% mGluR3, and 15% mGluR1. Incontrast, isolated CD4 /CD8 cells (double negative thymocyteprecursor) 45% expressed mGluR3 40%, and mGluR1whereas mGLuR5 was barely detectable. Therefore, it hasbeen hypothesized that changes in mGluRs subtypeexpressions may be related to T-cell maturation stages617,618.Human T-cells have been shown to express functionaliGluR3, indicating that both iGluR and mGluR are involved


in lymphocyte activation and possible control619.GluRs are also expressed in other lymphoid tissues and

inflammatory infiltrates12,102, and experimental evidenceindicates that human lymphocytes express iGluRsfunctionally operating as modulators of cell activation620.Glu is involved in signaling in immunocompetent cells andthat the expression of both iGluRs and mGluRs may haveregulatory functions in immunocompetent cells, as well as inthe nervous system. More recently it has been found that Glurelease by dendritic cells modulates T-cell activation621,622,indicating that the CNS and immune system are trulyconnected. In fact, it has been suggested that autoimmunityto GluR is central to altered cell modulation623.

NMDA-activated iGluR and mGluR1,4-8 are expressedin lymphocytes, and do induce functional changes. Levels ofexogenous and endogenous circulatory agonists andantagonists for lymphocyte GluRs, notably HC metabolites,are markedly increased in certain disease states and may beinvolved in disorders of the immune system624.

The global picture of how Glu interacts with theimmune system is still incomplete. As there is are a plethoraof chemical and electrical interactions in the cell and inhumoral mediated immunity, untangling the maze ofinteractions will be difficult. Nonetheless, the benefits offurther research in this area could benefit those inautoimmune or immune compromised states.

10. Reproductive organsDifferential distribution of GluRs has been shown in

reproductive organs of the male and female rat102. In thetestis, these receptors have a specific affinity for differentstructures. There is intense anti-mGluR2/3 immunolabelingof the head of the mature spermatids, spermatozoa,interstitial cells, myoid cells102, seminal vesicles37, and vasdeferens625. This distribution suggests that GluRs may beinvolved in spermatogenesis, spermatozoa motility,testicular development, and vas deferens control. In fact,GluRs might be important for the contractile activity of thevas deferens and hence in the control of seminal fluid625.

In the rat female reproductive system, GluRs also havea unique distribution within areas of the reproductive tract102.Antibodies have differential affinity to specific structures inthe ovaries, the fallopian tubes, the cervix, the myometriumand the endometrium. In the ovary the distribution of GluRswithin the follicles varies at different stages of theirmaturation102, an observation suggesting that these receptorsmay be involved in ovulation, fertilization, implantation ofthe ovum, and excitability of the uterus. The presence of theGluRs within the reproductive organs and the knownfunctional effects of GABA and GABA receptors626 suggestthat similar excitatory- inhibitory neurotransmissioninterplay may also be present in the reproductive organsusing GluRs as mediators.

It is possible that GluRs mediate some reproductivefunctions balanced with GABA receptor stimulation, such asgonadal maturation; steroidal sex hormone regulation;maturation, motility, and excitability of the spermatozoa627;

ovulation; fertilization; excitability of the fallopian tubes;implantation of the ovum; and excitabi l i ty of themyometrium—may be all affected.

Three key GluR subunits (NMDAR1, AMPA-GluR1and Ka-GluR6) fluctuate significantly during proestrus in therat628. However, treatment with the antiprogestin, RU486induces a significant elevation of GluR6 mRNA levelsduring proestrus, suggesting that endogenous progesteronemay act to inhibit hypothalamic GluR6 levels629 and thatthere might be co local izat ion of the AMPA andprogesterone receptors630. Similarly, estrogens, specificallyβ17-estradiol, are neuroprotective in a variety of modelsincluding Glu toxicity. Rat cortical neurons express NMDAand AMPA receptors, and are sensitive to brief periods ofexposure to anoxia-reoxygenation or Glu.

Pre t rea tment wi th e s t rogens a t t enua tes Gluexcitotoxicity and this protection is independent of theability of the steroid to bind the estrogen receptor631.Supporting this finding, testosterone and estradiol show astimulatory influence on the expression of AMPA receptorsin the hypothalamus, but there are site and genderd i f f e rences . Inc rease in hypo tha lamic GluR 2 / 3concentrations by estradiol stimulation have been reportedas two times higher in females, compared with males,whereas the changes in hypothalamic GluR1 levels showedno sex differences612.

Some research has been done on the developing fetusand Glu metabolism. The transport and metabolism ofglutamine and Glu exhibits unique characteristics thatclearly emphasize the importance of the interaction betweenthe placenta and the fetal liver632. Glutamine is deliveredinto the fetal circulation at a rate that is the highest of all theamino acids; however, the placenta extracts 90% of fetalplasma Glu.

Conversely, the fetal liver has a large net output of Glubut also uptakes glutamine. As development progresseschanges can be noted in both glutamine and Glu. Atparturition, a striking reduction in Glu output from the fetalliver occurs, leading to a fall in fetal arterial Gluconcentrations and a marked decrease in placental Gluuptake. This observation is correlated with a markeddecrease in progesterone output from the pregnant uterus632.

11. CardiovascularIn monkey and rat hearts, various GluRs have been

found in cardiac intramural nerve fibers and ganglia cells inthe conducting system633,634, and similar findings have beenseen in human hearts90. In these studies, antibodies toGluR2,3, GluR5-7, Ka2, and NMDAR1 showed the strongestsignals and were specifically localized to cardiac nerveterminals, ganglia, conducting fibers, and some tomyocardiocytes particularly in the atrium. Each antibodyportrayed a specific pattern of distribution98.

These structures are central to cardiac excitation andrhythmic control635–637. The presence on GluRs inmyocardium, conducting system, nerve fibers and intramuralganglia cells in all three species, strongly supports the view

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that these receptors may play a role in the physiology andpathophysiology of cardiac rhythm and excitation90,638.

L-Glu increases the frequency of Ca++ oscillations639,which have been positively correlated with increasedcontraction frequency in myocardial cells. Such an increasecould reduce cardiac filling, hypoxia and angina-like chestpains. In fact, non-NMDA, but not NMDA and mGluRs inthe commissural nucleus of the solitary tract play animportant role in the sympathoexcitatory reflex response toactivation of cardiac receptors during myocardialischemia640. It is likely that the concentration of Glu and thenumber of GluR will modulate this effect641.

Experimental evaluation of the effect of Glu on bloodpressure in anesthetized rats showed that followingintrathecal injection of mGluR agonists at the thoracolumbarlevel of the spinal cord, activated Group I, II and III mGluRs(mGluR1-8), and increased the mean blood pressure. Incontrast, low doses of Group II mGluR (mGluR2/3) agonistsinduce hypotension and bradycardia following blockade ofNMDA receptors642. It is possible that modulation of Gluand GluR could be used in the future for amelioratinghypoxic cardiovascular disease and hypertension. In the reallife situation, cardiac lesions have been seen in sea lions thatdied of DMA toxicity along the coast of California189,644,645

implying that EAAs and Glu play and important role incardiac pathology.

12. LungsAdult respiratory distress syndrome [ARDS], where

excessive activation of the NMDAR1 in the lungs inducesacute edema and lung injury105,646, is often a fatal disorder.The injury in ARDS can further be modulated by blockage ofone of three critical steps: NMDA1 binding, inhibition of NOs y n t h e s i s , o r a c t i v a t i o n o f p o l y ( A D P - r i b o s e )polymerase105,646. Immunolabeling for various GluRs inbronchial epithelium, blood vessels of the lungs, mast cells,and inflammatory cells has been reported90, which supportsthe view that GluRs play a role in airway responses to injuryand inflammation.

Their presence in the airway structures such as thelarynx, esophagus and mast cells also implicate the GluRs inthe mediation of asthmatic episodes33,105,646. The excitationof GluRs in the air passages therefore may be important inairway inflammation and hyper reactivity observed inbronchial asthma647. Their presence also could explain theenhancement of acute asthmatic attacks by Glu-containingfoods33.

Mast cells, central to histamine release and asthma, arefound in the connective tissues throughout the body.Spermidine-induced release from the mast cells is dependenton the presence of Ca++ in the external milieu648. The influxof Ca++ following spermidine administration is accompaniedby NMDAR1 activation, and the increased intracellular Ca++

concentration initiates the exocytotic degranulation processin mast cells and release of histamine.

Spermine is a natural polyamine, and binding sites forpolyamines facilitates the opening of the ion channel

associated with NMDA receptors. In neuronal tissue,polyamine triggers histamine secretion through interactionwith a polyamine site associated with an NMDAR1 macrocomplex. Therefore, spermine can modulate activation ofthe macro complex, either through action at polyamine-binding sites in the lung or at other sites. The antagonists ofNMDAR1 block this release of histamine secretion that wasinduced by the natural polyamine-spermine. When theNMDAR1 is present it is possible that EAAs can alsoinfluence allergic reactions.

13. Kidneys and liverThe wide distribution of NMDAR1 and the presence of

mGluR2/3 and AMPA-GluR2,3 in the juxtaglomerularapparatus [JGA] and proximal tubules102, suggests that thesereceptors may be involved in electrolyte and waterhomeostasis, probably associated with the control of reninrelease649.

Dopamine receptors [DARs] are also specificallydistributed where D1A and D1B are reported to be present inthe renal vasculature, renal proximal and distal convolutedtubules , cor t ica l , and co l lec t ing duc ts . In fac t ,pharmacological and biochemical evidence also supports thepresence of the DARs—D1A, D1B, D2, and D3 within thekidney92,650,651. In contrast, D1A is not present in JGA and theascending loop of Henle, whereas D1B is present in theseregions. Experimental data suggests that DARs are involvedin rena l hemodynamics , ion t ranspor t and ren insecretion92,650,651.

In addition to the GluRs and the DARs, GABAA andGABAB receptors have been localized to the renal cortex134.Therefore, GABA might also balance the effects of GluRs onrenal functions within in the kidney cortex rather than themedulla.

H e p a t i c i G l u R s a n d m G l u R s h av e b ee ndemonstrated98,99. In vitro, mGluR5 in primary culturedhepatocytes s t imulates the hydrolysis of inosi tolphospholipids99. The effects of mGluRs agonists wereexamined with anoxia-induced cell damage, where theagonists reduced the viability of hypoxic hepatocytescompared with controls. But not all agonists had this effect.It has been suggested that GluR is activated by the Glupresent in the portal blood and may contribute to the liverdamage under adverse conditions.

14. Gastrointestinal tractGluRs have been reported in the stomach, duodenum

and descending colon, of the gastrointestinal tract[GIT] 9 1 , 9 5 – 9 7 , 6 5 2 where s t a in ing was seen in theenteroendocrine cells, ganglia cells and nerve fibers havebeen seen throughout the GIT653. Glu induces contraction ofthe ileal longitudinal smooth muscle and myenteric plexus96,and mGluRs play a role in neurotransmission83 and in theenteric reflexes, where Glu, GABA and NMDA receptors95

are involved intestinal motility at the myenteric plexus, asvesicular Glu transporters [VGLUT]600,654, in muscle655 andin the stomach contractions656. These effects can be blocked


noncompetitively by NMDA but not by Ka or quisqualateantagonists657.

In the CNS, electrophysiological L-Glu and L-Asp areless potent than NMDA due to their avid uptake by thetissue102, but there appears to be an absence of the uptakeprocesses of these compounds in the myenteric plexus95,96.However, Glu and Asp are both involved in regulating acidsecretion in the stomach, but the mode of action of each isdifferent652,658. Asp was more specific than Glu in regulatingacid secretion. This was attributed to the fact that Glu is ageneral agonist for all types of GluRs, yet Asp is a potentagonist for NMDAR receptors. Interestingly, NMDAreceptor influences opioid release from enteric neurons659.

Glu, GluRs, and GluTs also act in a more centralmanner in the GIT tract via the vagus660, where afferentvagal transmission is done via the left vagal afferent fibersvia nonNMDA receptors to neurons661. In addition, theeffect on vagal activity impacts the hepatoportal andpancreatic systems through either up regulating or downregulating vagal activity. It has been suggested also that thiseffect may account for the GIT upsets experience by someindividuals following ingestion of MSG662.

The application of knowledge regarding the Glu systemmay lie in its potential prognostic value in some neoplasia,investigating Glu analogues, and irritable bowel syndrome[IBS]. Initial work along this track has shown that mGluR4signaling is seen in colorectal carcinomas, and that overexpression of mGluR4 is associated with a poor prognosis124.There is some question as to whether the dorsal horn neuronsmay be involved in intestinal motility, where antagonizingGluR corresponds to colonic distension663. The practicalimplication of this finding may lie in treatment of IBS.

15. MusculoskeletalAlthough it has been recognized that muscle stores Glu,

most work on GluRs has been done in invertebrates664.However, there are some reports of research done inmammals, particularly in the realm of muscular paincontrol665. In fact, most work on muscles has been onsmooth muscle in other organs such as the gastrointestinaltract666, and of course, the nervous system effects onmuscle667.

Bone has been shown to contain different GluRssubunits: GluR2,3, NMDAR1, mGluR2,4,5&7

668, and bone cellshave the potential to express many of the moleculesassociated with the Glu-mediated signaling669,670. In fact, ithas been suggested that GluRs in bone are a novel means ofparacrine communication in the skeleton671, although there isstill a question regarding the role of Glu in controlling bonegrowth672.

Nonetheless, all osteoblasts673,674. osteocytes, andosteoclasts express one or more of the GluRs subunits111,675,and intrinsic control of Glu signaling occurs by releasingGlu676. Interestingly, NMDA type Glu receptors expressedby primary rat osteoblasts have the same electrophysiologicalcharacteristics as neuronal receptors677,678. The blockade ofNMDA receptors with antagonists results in inhibition of

osteoblast formation, suggesting that most abundantNMDAR1 is functional in bone679 and that it is involved inosteoclast differentiation680. So, although total control ofbone growth is not under Glu control, it certainly seems asthough Glu, GluRs, and GluTs affect individual cell types.

GLAST has also been identified in bone111, furthersupporting the view that EAAs may play a role in paracrinesignaling in bone cells681. The GLAST performs an essentialfunction during Glu-mediated synaptic neurotransmissionby acting as a high affinity uptake system to remove releasedGlu from the synaptic cleft, thus preventing over stimulationof the postsynaptic Glu receptors682.

16. SkinMost of the literature regarding the functional effects of

GluR and skin relates to pain as an endpoint. However,GluRs have been reported in skin112 and keratinocytes101,683.So far mGluRs and iGluRs, including NMDA and AMPA,have been described100 and there are suggestions thatdesensitization of GluRs may contribute to tolerance seen ins e n so r m o t o r c o n n e c t i o n s f o l l o w i n g m u l t i p l estimulations684,685.

It appears as though Group II mGluR2/3 are involved inthis process686,687. Interestingly, mGluR5 have been foundon human melenocytes; however, their action is stilluncertain, but has been hypothesized to be in the control ofmelenocyte proliferation688. Perhaps we will understand therole of mGluR5 in melanomas in the future, so eventuallyGluR might be used in prognostication and treatment ofthese malignancies.

Taste: Taste receptor cells [TRCs] are specializedepithelial cells that are clustered together into ovoid endorgans located in the epithelium of the tongue, the softpalate, and the epiglottis681. On the tongue, taste buds arefound in fungiform, foliate, and vallate taste papillae. Boththe detection of chemical stimuli and the synaptic activityrely on the presence of specific membrane proteins689,690.Among these proteins, GluRs play a key role in TRCs’physiology691, acting as molecular sensors for food L-Gluand as synaptic receptors in glutamatergic interactions withnerve endings692. Indeed, messenger RNAs encodingseveral ionotropic subunits and an mGluR4-like receptorhave been identified in taste papillae693,694, and are probablystimulated by MSG88. Of the Glu and GluR, the NMDAreceptor serves as a primary taste transducer for MSG, andan mGluR modulates the flavor enhancing effect of MSG695.

Summary and Conclusions

Glutamate is the most common neurotransmitters, as L-glutamic acid is present in most foods, found in either thefree form or bound to peptides and proteins. In fact, the Glusystem is ubiquitous across most animal taxa and has beenfound in plants. The most abundant molecular component ofthe Glu system is NAAG.

Glutamate receptors perform a variety of functions inthe central and peripheral nervous systems such as learning,

Rousseaux 153

memory, anxiety, and the perception of pain. They consistof two subtypes: ionotropic and metabotropic glutamatereceptors. iGluRs are a group of transmembrane ionchannels that open in response to NMDA, Ka and AMPA.mGluRs are active through an indirect metabotropic process.They are members of the Group C family of G-protein-coupled receptors the activation of which has beenestablished to be neuroprotective in vitro and in vivo. UnlikeiGluRs, mGluRs are not directly linked to ion channels, butmay affect them by activating biochemical cascades.

Endogenous Glu, by activating NMDA, AMPA ormGluR1 receptors, may contribute to the brain damageoccurring acutely after status epilepticus, cerebral ischemiaor traumatic brain injury. Endogenous Glu may alsocontribute to chronic neurodegeneration in such disorders asALS, AD, PD, MS, and HD. Other clinical conditions thatmay respond to drugs acting on glutamatergic transmissioninclude epilepsy, amnesia, anxiety, hyperalgesia andpsychosis.

Although the CNS, PNS and ANS are the regions wheremost work has been done identifying the GluRs and theiragonistic and antagonistic effects, a reasonable amount ofdata is available for review for other tissues. Regardless ofthe current information available, there are many missingpieces in the Glu, GluR and GluT picture, which hopefullywill be clarified in the not too distant future. These missingpieces will be necessary to fully describe the function andstructure of the Glu system. It is quite probable that in yearsto come we will understand that the Glu system plays a morecentral role in many more disease entities than have beeninvestigated thus far.

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a review of glutamate receptors ii - j-stage

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