Receptors & Transmitters

Basic Neuroscience NBL 120 (2007)

locks & keys

You are a neurotransmitter if you….

are produced within a neuron, and are present in the presynaptic terminal

are released during depolarization (action potential-dependent)

act on receptors to cause a biological effect

have a mechanism of termination

More strictly, to be a transmitter..

a particular substance, when applied to the post-synaptic cell in quantities equal to that released by the pre-synaptic cell, produces the same post-synaptic response as does a pre-synaptic action potential

The keys

Small molecular weight: Acetylcholine (ACh) Amino acids:

Glutamate, GABA, glycine

Biogenic amines: Catecholamines:

Dopamine, Norepinephrine (Epinephrine)

Indolamines: Serotonin (5-HT), Histamine

Nucleotides ATP , Adenosine

More keys...

Neuropeptides

Unconventional (what?) (yes, I want to be a transmitter but I’m not

going to tell you exactly how)

Small Molecules

Neuropeptides

Back to transmission…..

Amino Acids

Glutamate everywhere in CNS major excitatory transmitter in CNS most projection neurons in cortex use glutamate

GABA everywhere in CNS major inhibitory transmitter in CNS found (not always) in local circuit neurons (interneurons)

Glycine major inhibitory transmitter in brainstem and spinal cord

glutamate

Synthesis and Degradation: GABASynthesis and Degradation: GABA

Kreb’sCycle

-ketoglutarate glutamate

GABA(release & uptake)

The GABA Shunt

glutamic aciddecarboxylase (GAD)

succinic semialdehyde

succinic acid

Distribution: Acetylcholine 5%Distribution: Acetylcholine 5%Ventral horn spinalmotoneurons (PNS)to skeletal muscleBrain stem motor nucleiStriatum (local)Septal nuclei to hippocampusNucleus basalis to cortex, amygdala, thalamusPNS - autonomic

Cognition - memoryMotor (striatum)

locus coeruleus to everywhere

attention, alertness circadian rhythms memory formationmood

Distribution: Norepinephrine (NE) 1%

Rostral raphe nuclei to nearly all regions of the brainCaudal raphe nuclei to spinal cord

moodsleep / wake cyclespain modulation

Distribrution: serotonin (5-HT) 1%

Substantia nigra to striatumVentral tegmentum to: amygdala nucleus accumbens prefrontal cortexArcuate nucleus to median eminence of hypothalamus

movementmotivationsex hormones

Distribution: Dopamine 3%

DopamineTyrosine

L-DOPA

tyrosinehydroxylase

dopa decarboxylase

HO CH2-CH-NH3

COOH+

HO CH2-CH-NH3

COOH

OH

+

HO

OH

CH2-CH-NH3

H+

(these steps occur within the cytoplasm)

Sythesis: Dopamine

dopamine--hydroxylase(DBH)

Dopamine

Norepinephrine

HO

OH

CH2-CH-NH3

H+

HO

OH

CH-CH2-NH3

OH+

(these steps occur within the synaptic vesicle)

Synthesis: Norepinephrine

Transmitter termination

Clinical relevance: Neurotransmitter transporters:

MAOs: disease (epilepsy, ALS, Parkinson’s)

drug abuse (cocaine, amphetamine)

treatment (depression, OCD)

Classes of Neurotransmitter Receptors

Ionotropic Receptors Ligand-gated ion channels Fast synaptic transmission (1 ms) Are closed (impermeable to ions) in absence of transmitter Neurotransmitter binding opens receptor (direct)

Metabotropic Receptors G-protein coupled receptors (GPCRs) Slow onset and longer duration of effects (100 ms & longer) Ligand binding activates GTP-binding proteins (indirect)

Definitions…

Agonist = activates (opens) the receptor when it binds Antagonist = binds to the receptor and inhibits its function

different types

Allosteric modulators = act at a site different from agonist Desensitization = response decrease although the agonist is still

present or repetitively applied Ligand gated ion channels:

Gating = opening / closing of the channel Kinetics = how long processes take Affinity = tightness of the agonist binding Efficacy = how readily the channel opens

Ligand-gated / G-protein Coupled

Transmitter and receptor pairing

Both ionotropic and metabotropic receptors: glutamate acetylcholine GABA 5HT (serotonin)

Just ionotropic: glycine

Just metabotropic: other biogenic amines (DA & NE)

Each subunit has multiple membrane spanning domainsGlutamate: 3All others: 4

MultimersGlutamate: 4All others: 5

Glutamate Receptor Subunits All Other Receptor Subunits

Ligand-gated ion channels

Binding sites on GABA receptors

Opening of the channel requires GABA

The other sites are “allosteric” for GABA binding

Congenital myesthenia

Single channel lifetime shortened

- opening rate decreased

- closing rate increased

(Wang et al, 1999)

Receptors G Proteins Effectors

Metabotropic Receptor

G Proteinaka

GTP binding protein

heterotrimeric G protein

large G protein

Effectorsadenylyl cyclase

phospholipase C

cGMP phosphodiesterase

phosphoinositol-3-kinase

Ca2+ channels

K+ channels

Na+ channels

Structure of G-protein Coupled Receptors

Single polypeptide with 7 TM domains (no subunits)

2nd & 3rd cytoplasmic loops plus part of the intracellular tail bind to appropriate G protein

Agonist binding causes conformational change that activates the G-protein

cholera toxin

pertussis toxin

Direct modulation of Ca2+ channels

Modulation Through 2nd Messenger Pathway

“retro” transmitters

NO

endocannanbinoids