Neurotransmitters

PY 10.10 Describe and discuss chemical

transmission in the nervous system.

Dr Shehin M
Assistant Professor
Physiology
Neurotransmitters
• Chemical agents responsible for impulse conduction through synapse
E.g. Glutamate, GABA, Aspartate, Glycine
• Neurosecretions/Neurohormones: Chemical agents synthesized in
neurons & discharged in blood circulation, CSF or intracellular spaces
E.g. NE, ADH, GnRH
• Neuromodulators: Chemicals released by neurons that modify the
effects of neurotransmitters, but have no direct effect on its own
E.g. Substance P, VIP, CCK
Criteria of Neurotransmitter
1. Synthesized in pre synaptic neuron, stored in synaptic vesicles &
released on nerve stimulation
2. Enzymes for its inactivation should be present
3. When externally used, neurotransmitter should mimic the effects of
nerve stimulation
4. Drug modifying the effect of nerve stimulation should have same
actions as of neurotransmitter
Classification of Neurotransmitters
Physiological Classification of Neurotransmitters

Classification Neurotransmitters

Excitatory Neurotransmitter Ach, Aspartate, Glutamate

Inhibitory Neurotransmitter GABA, Glycine, Dopamine

Classification of Neurotransmitters
Biochemical Classification of Neurotransmitters

Classification Agents

Amino acids (Glutamate,GABA, Glycine)

Small-Molecule Transmitters Acetylcholine

Monoamines (NE, E, DA, Serotonin)

Large-Molecule Transmitters Substance P, Enkephalin & Vasopressin

Gas Transmitters NO, CO

Receptors
Autoreceptors & Heteroreceptors
• Autoreceptors: Presynaptic receptor which inhibits further release of
transmitter
Eg.NE acts on α2-presynaptic receptors to inhibit additional NE release
• Heteroreceptors: Ligand which binds to these presynaptic receptors is
a chemical different from neurotransmitter released by pre-synaptic
terminal
E.g. NE binds to heteroreceptor on cholinergic neuron to inhibit release
of ACh
Receptors
Ionotropic & Metabotropic Receptors
• Ionotropic Receptors: Membrane channel opens when a ligand binds
to receptor (Important for fast synaptic transmission)
• Metabotropic Receptors: Binding of neurotransmitter to
transmembrane receptors (GPCR) lead to activation of G-protein
which produces 2nd messenger
Glutamate
• Most prevalent excitatory neurotransmitter (75%)
• Site: Brain & dorsal sensory nerve terminals
Synthesis of Glutamate
• From α-ketoglutarate
By Kreb’s cycle α-ketoglutarate
↓ GABA transaminase (GABA-T)
Glutamate
• From glutamine
Glutamine
↓ Glutaminase
Glutamate
Fate of Glutamate
• Released in synaptic cleft by Ca2+ dependent exocytosis
• Acts on ionotropic & GPCRs on post-synaptic membrane
• Taken back by Na+ dependent glutamate reuptake transporter on
synaptic terminals & glial cells
• In glial cells, glutamine synthetase converts glutamate to glutamine
• Glutamine diffuses back in nerve terminal, where glutaminase
hydrolyzes it back to glutamate
• Glutamate is concentrated in synaptic vesicle by vesicular glutamate
transporter
Degradation of Glutamate
• Glutamate dehydrogenase converts glutamate to GABA
Glutamate Receptors
• Ionotropic Receptors
1. AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionate)
receptor: 4 AMPA subunits (GluR1-R4)
2. Kainate: 5 kainate subunits (GluR5-R7, KA1, KA2)
3. NMDA (N-methyl-D-aspartate) receptor: 6 NMDA subunits (NR1,
NR2A-NR2D)
• Metabotropic Receptors: mGluR1, mGluR5, mGluR2, mGluR3,
mGluR4, mGluR6-7
Location of Receptors
• Kainate & AMPA Receptors: Glial cells & neurons
• NMDA receptors: Neurons
 Mechanism of Action of
Receptors
Glutamate binds to AMPA & kainate receptors
↓
Infux of Na+ & efflux of K+
↓
Development of EPSP

Glutamate binds to NMDA receptors

↓
Influx of Na+ and Ca2+ & efflux of K+
Role of Receptors
• Ionotropic Receptors:
 Concentration of NMDA receptors is more in hippocampus
 Role in LTP (Long term potentiation): Memory & learning
• Metabotropic Receptors:
 Synaptic plasticity in hippocampus & cerebellum
Antagonists of Glutamate
• NMDA receptor antagonist:
1. Memantine: Alzheimer disease
2. Amantadine: Parkinson disease
3. Riluzole: Amyotrophic lateral sclerosis (ALS)
Gamma Amino Butyric Acid (GABA)
• Synthesis: From glutamate by glutamate decarboxylase (GAD)
• Receptors: GABAA & GABAB are present in CNS & GABAC in retina
Mechanism of Action of GABA
• GABAA & GABAC: Ionotropic receptors→ Cl- infux→ Production of IPSP
• GABAB: Metabotropic receptors → K+ efflux & slows Ca2+ influx
Mediates both presynaptic & slow postsynaptic inhibition
Applied Aspect of GABA
• Treatment of epilepsy: Benzodiazepines like Diazepam (Act as anti
anxiety, anti convulsant, sedative & muscle relaxant)
• Barbiturates like Phenobarbital (Anticonvulsants)
• Barbiturates like Thiopental (Anaesthetic action)
Glycine
• Both excitatory & inhibitory effects in CNS
• Excitatory action: Bind to NMDA receptor & makes them more
sensitive to glutamate
• Inhibitory effect: By increasing Cl- conductance
• Involved in Renshaw cell inhibition
• Applied aspect: Strychnine blocks glycine receptors & leads to
muscular hyperactivity & convulsions
Acetylcholine
• Location
1. Neuromuscular junction
2. Pre ganglionic autonomic neurons
3. Post ganglionic parasympathetic neurons
4. Post ganglionic sympathetic neurons supplying sweat glands,
skeletal muscle blood vessels
• Receptors: Muscarinic & nicotinic receptors
Catecholamines
• Norepinephrine, Epinephrine & Dopamine
• Receptors: α & β adrenoreceptors
Fate of Catecholamines
• Epinephrine & Norepinephrine are oxidized & methylated by MAO
(Monoamine oxidase) & COMT (Catechol-O-methyltransferase)
• O-methylated derivatives: Normetanephrine & Metanephrine
• Most abundant metabolite in urine: Vanillylmandelic acid (VMA)
Dopamine
• Location
1. Nigrostriatal system
2. Mesocortical system
• Receptors
1. D1-like (D1 & D5)
2. D2-like (D2, D3 & D4)
Applied Aspect
• Overstimulation of D2 receptors → Schizophrenia
• Symptoms: Hallucinations, delusions & loss of motivation
• Treatment
1. Dopamine antagonists: Chlorpromazine, Haloperidol
2. Atypical Antipsychotics: Clozapine, Risperidone, Olanzapine
Serotonin
• 5-Hydroxytryptamine or 5-HT
• Location: Enterochromaffin cells, Platelets, myenteric plexus in GIT,
raphe nuclei in brainstem
• Receptors: 5HT1 – 5HT7 are GPCRs (except 5-HT3)
• Applied aspect: SSRI (Selective serotonin reuptake inhibitors) are used
in treatment of depression
Synthesis of Serotonin
Tryptophan
↓ Tryptophan hydroxylase
5-Hydroxytryptophan
↓ Decarboxylase
Serotonin
Essays
1. Classify synapse. Mention the various properties of synapse. Add a
note on central neurotransmitters.
2. Classify synapses and describe the mechanism of transmission
across the synapse. Mention the various properties of synapse. Add
a note on central neurotransmitters.
Short Answers
1. Name two facilitatory and inhibitory neurotransmitters and their
sites of action.
2. Name two facilitatory and inhibitory neurotransmitters.
3. Acetyl choline
4. What are Cholinergic & Adrenergic receptors?
5. Dopamine
Multiple Choice Questions
1. The neurotransmitter that is excitatory is
A. Glycine
B. Glutamate
C. Serotonin
D. Dopamine
Multiple Choice Questions
2. Neurotransmitter responsible for pre-synaptic inhibition is
A. Glycine
B. Glutamic acid
C. Serotonin
D. GABA
Thank you