neurotransmitters. a chemical released by one neuron that affects another neuron or an effector...
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Neurotransmitters
A chemical released by one neuron that affects another neuron or an effector organ (e.g., muscle, gland, blood vessel)
• Excitatory neurotransmitters – cause depolarization• Inhibitory neurotransmitters
– cause hyperpolarization
Neurotransmitters
Attributes of “classical” neurotransmitters
Synthesized in the presynaptic cell Stored in membrane-bound vesicles
(synaptic vesicles) Released from the presynaptic vesicle in
response to membrane depolarization Induction of a physiological response in the
post synaptic cell (by depolarizing or hyperpolarizing its membrane)
inactivated (rapidly) in the synaptic cleft
Classification of neurotransmitters
GROUP EXAMPLES amines acetylcholine (Ach),
norepinephrine, epinephrine, dopamine, 5-HT
amino acids glutamate, GABApurines ATP, adenosinegases nitric oxidepeptides endorphins, tachykinins, many
others
EXCITATORYAcetylcholine GlutamateNorepinephrine AspartateEpinephrine Histamine
INHIBITORYGABA Glycine
MIXEDDopamine Serotonin
Excitatory/inhibitory neurotransmitters
Release of neurotransmitters
Neurotransmitters bind to receptors
Ionotrophic receptors: these act as ion channel themselves to produce their effects.
Metabotrophic receptors: these activate second messenger system (cAMP, PIP3) to produce their effects.
biogenic amines
Neurotransmitters – biogenic amines
Catecholamines• Dopamine• Norepinephrine• Epinephrine
Indoleamines• Serotonin (5-HT)• Melatonin
Catecholamines – functionsDopamine: control of voluntary movement (nigrostriatal tract), emotional responses and memory (limbic system)
Norepinephrine: “fight or flight response” such as stimulation of heart rate, sweating, skin vasoconstriction and bronchodilation (sympathetic nervous system), state of alertness (brain stem)
Epinephrine: response to stress, redirection of blood from skin to heart, glycogen metabolism, blood pressure (adrenal medulla under influence of Ach-containing nerves)
Tyrosine
L-Dihyroxyphenylalanine (DOPA)
Tyrosine hydroxylaseBH4
BH2
Dopamine
Dopa decarboxylase PLPCO2
Norepinephrine
Dopamine β hydroxylase Cu++, Vit CO2
NEU
RON
SAD
RENAL M
EDU
LLA
Epinephrine
Phenylethanolamine N-methyltransferase
SAM
SAH
Vit B12 Folate
Catecholamines - Synthesis
Parkinson’s disease
• Degeneration of nigrostriatal dopamine neurons in the brain resulting in a deficiency of Dopamine
• Symptoms include trembling of hands, arms, legs, jaw and face; stiffness of the arms, legs and trunk; slowness of movement; poor balance and coordination
• Treatment with L-DOPA which enters the brain and is decarboxylated to dopamine.
• L-DOPA is given together with carbidopa, DOPA carboxylase inhibitor that cannot enter the brain, preventing unwanted formation of dopamine outside the brain
Serotonin: involved with mood, anxiety, appetite, sleep induction, memory and learning
Melatonin: involved in response to light-dark cycle organizing seasonal and circadian rhythms, regulating reproductive functions
Indoleamines – functions
Tryptophan
5’hyroxytryptophan
Tryptophan hydroxylaseBH4
BH2
Serotonin
Dopa decarboxylase PLPCO2
Vit B12 Folate
Synthesis – indoleamines
Acetyl CoA
Melatonin
SAM
SAH
CoASH
Degradation–Norepinephrine
Degradation–monoamines Norepinephrine
epinephrine
Vanillylmandelic acid
Dopamine
Homovanillic acid
Serotonin
Hydroxyindoleaceticacid
MAO-A,-BCOMT
MAO-BCOMT
MAO-A
Endocrine tumors (pheochromocytoma, Carcinoid syndrome) diagnosed by the measurements of these breakdown products in urine.
monoamines- release and uptake
Monoamines and depression
• “amine theory of depression” states that depression is caused by a relative deficiency of amine neuro-transmitters at central synapses
• Prevention of catabolism of catecholamines and serotonin reduce depression by elevating the levels of these compounds. MAOA inhibitors act as antidepressants
• Inhibitors of norepinephrine and serotonin transport into neurons also act as antidepressants (e.g. prozac; serotonin reuptake inhibitor)
Histamine
Histamine – Functions
• Dilates blood vessels, increases capillary permeability, contracts bronchial and intestinal smooth muscle, stimulates gastric acid secretion and nasal fluid discharge
Histamine - synthesis and degradation
Acetylcholine
Acetylcholine - functions
• Major neurotransmitter at the neuromuscular junctions to induce muscle contraction
• Play an important role in attention, learning, reward pathways and memory by reinforcing the ability to detect and respond to meaningful stimuli
Neurons associated with Ach degenerate in Alzheimer's disease resulting in declining language and perception, confusion and memory loss.
Acetylcholine – synthesis and degeneration
Acetylcholine- release and inactivation
Disorders of acetylcholine metabolism
Myasthenia gravis: a disease characterized by muscle weakness. Autoimmune disorder due to formation of antibodies against the nicotinic Ach recptors, preventing trnsmission of nerve impulses to muscles. Treated by inhibitors of Ach esterase (pyridostigmine, neostimine) and corticosteroids
Lambert-Eaton myasthenic syndrome: autoimmune disorder also characterized by muscle weakness. Due to auto-antibodies against the presynaptic voltage-gated calcium channels
Acetylcholinesterase inhibitors
• Organophosphate insecticides and nerve gases (sarin) inhibit acetylcholinesterase resulting in an excess of Ach, initially causing uncontrolled muscle contraction and eventually paralysis. Treatment by atropine.
Amino acids as neurotransmitters
Amino acids as neurotransmittersRecruited as neurotransmitters by packaging into
synaptic vesicles Their action is terminated by sodium dependent
high affinity uptake with need for any specific degradative enzymes
EXICTATORY INHIBITORYGlutamate GlycineAspartate GABA
Glutamate/GABA - synthesis
Inhibitors of Amino Acid NT
Benzodiazapines (valium, Xanax) bind GABA receptors reducing anxiety, inducing sleep and guarding against seizures (anticonvulsants)
Barbiturates produce a wide spectrum of effects, from mild sedation to total anesthesia by potentiating inhibitory GABA receptors and inhibiting excitatory AMPA glutamate receptors
Strychnine binds to glycine rectorss leading to convulsions, spastic contraction of skeletal muscles and death due to impairment ot muscles of respiration.
NITRIC OXIDE
NITRIC OXIDE
NO is not stored in vesicles but released directly into the extracellular space
Functions• Relaxation of vascular and intestinal smooth
muscle• Neural transmission• Regulation of mitochondrial energy production• Cytotoxic action on parasites and tumor cells
NITRIC OXIDE - synthesis
Peptides
Peptides
Over 80 peptides shown to influence neural functionsSynthesized as precursor proteins, packaged into vesicles and cleaved to the active form by peptidases
e.g.Opioids peptides (endorphins, enkephalins)Regulate pain and pleasure pathways Substance P transmits signals in response to pain
Opioid receptors are sites of action for morphine and codeine which are powerful analgesics
Opiates affect pleasure pathways in the brain resulting in the associated euphoric effects. Endorphins released after strenuous exercise give the so-called “jogger's high”
Peptides inhibitors
the end!!