Cholinergic transmission involves the synthesis of acetylcholine (ACh) from choline and acetyl-CoA by the enzyme choline acetyltransferase (ChAT). ACh is stored in synaptic vesicles and released into the synaptic cleft upon neuronal stimulation. It acts on nicotinic and muscarinic receptors. Nicotinic receptors are ligand-gated ion channels that allow cation influx, while muscarinic receptors are G protein-coupled receptors that activate various intracellular effector pathways. After acting as a neurotransmitter, ACh is rapidly hydrolyzed by acetylcholinesterase to terminate its effects. Disorders of the cholinergic system can impact cognitive function, muscle contraction, and other processes.

1. CHOLINERGIC
TRANSMISSION
&
RECEPTOR
PHARMACOLOGY
Dr. Jayesh Vaghela
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2. CHOLINERGIC
TRANSMISSION
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3. CholineAcetylTransferase ( ChAT )
• Catalyzes the final step in the synthesis of Ach
i.e.- Acetylation of Choline with Acetyl CoA
• Acetyl CoA ⇒ from pyruvate via pyruvate dehydrogenase
reaction
- In mitochondria at axonal terminals
• Choline ⇒ Reuptake after release
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4. Perikaryon ChAT
AxonalTerminal Acetyl CoA Choline
Cytoplasm ACh
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5. Choline & ItsTransport
• Choline: - Available from diet
- Essential for normal function of cells
- Structural integrity
- Signaling functions of cell membranes
• 2Transport Mechanisms
- Na+ independent transport system
- Na+ & Cl- dependent transport system
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Predominant,
Provide Choline for
Ach synthesis

6. CholineTransporter [ CHT 1 ]
• Homologous to Na+ dependent glucose transport family
• Location: - Intracellular vesicular structures
- Co-localizes with,
-VAMP2–Vesicle-associated membrane protein
-VAChT -Vesicular AChTransporter
• During transmitter release events ⇒ ↑edTrafficking of CHT1 to plasma membrane
⇓
Takes up Choline after ACh hydrolysis
⇓
↑ed ACh Stores to maintain high levels of transmitter release
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7. Storage of ACh
• Synthesis of ACh in cytoplasm
• Transported into synaptic vesicles byVAChT using proton electrochemical
gradient
• Proton comes out of the vesicles & ACh moves in.
• Two types of vesicles
 Electron-lucent vesicles
 Dense-cored vesicles
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8. • Content:
 ACh
 ATP
 Vesiculin ( proteoglycan )
 Peptides, e.g.VIP
• Single motor nerve terminal contains about 3,00,000 or more vesicles
• Each vesicle having 1000 to 50,000 ACh molecules
• Also some extravesicular cytoplasmic ACh
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9. Release of ACh
Depolarization of nerve terminal
⇓
Ca++ entry through voltage-gated calcium channels
⇓
Fusion of vesicular membrane with plasma membrane
⇓
Release of ACh & co-transmitters via exocytosis
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10. Molecular mechanism of ACh release
ACh is stored in vesicles at presynaptic membranes,
Ready to release after appropriate stimulus
⇓
Docking & Priming of vesicles
⇓
Multiprotein complex attaches the vesicles to plasma membrane
( Syntaxin, Synaptobrevin, SNAP-25 )
⇓
Fusion of vesicles & Release of ACh by exocytosis
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11. Pools of ACh
• Depot / Readily releasable pool :
- contain newly synthesized ACh.
- Depolarization ⇨ rapid release of ACh
• Reserve pool :
- Replenishes the depot pool
- Sustained ACh release during prolonged nerve stimulation
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12. Acetylcholinesterase ( AChE )
• ACh must be removed or inactivated after its action to serve as
neurotransmitter in motor system
• At neuromuscular junction, immediate removal is required-
-To prevent lateral diffusion
-To prevent sequential activation of adjacent receptors
• Less than a millisecond is required to hydrolyze ACh by AChE
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13. Characteristic Acetylcholinesterase (True ) Butyrylcholinesterase ( Pseudo )
Distribution - All cholinergic sites
- RBCs
- Gray matter
- Plasma
- Liver
- Intestine
- White matter
Hydrolysis of-
- ACh
- Methacholine
- Benzoylcholine
- Butyrylcholine
- Very fast
- Slower than ACh
- Not hydrolyzed
- Not hydrolyzed
- Slow
- Not hydrolyzed
- Hydrolyzed
- Hydrolyzed
Inhibition More sensitive to
Physostigmine
More sensitive to
Organophosphates
Function Termination ofACh action Hydrolysis of ingested esters
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15. NICOTINIC
ACh
RECEPTORS
( nAChR )
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19. Receptor Location Response Mechanism Agonist Antagonist
Skeletal
muscle
NM
Adult (α1)2
β1εδ
Fetal (α1)2
β1γδ
Skeletal
neuromuscular
junction,
Postjunctional
Excitatory :
- End plate
depolarization
- Skeletal muscle
contraction
↑ed cation
permeability
( Na+ , K+ )
ACh
Nicotine
Succinylcholine
Atracurium
Vecuronium
d-TC
Pancuronium
α-conotoxin
α-bungarotoxin
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20. Receptor Location Response Mechanism Agonist Antagonist
Peripheral
neuronal
NN
(α3)2(β4)3
Autonomic
ganglia
Adrenal medulla
Excitatory:
Depolarization:
Firing of
postganglionic
neuron;
Secretion of
catecholamines
↑ed cation
permeability
( Na+ , K+ )
ACh
Nicotine
Epibatidine
Trimetharphan
Mecamylamine
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21. Receptor Location Response Mechanism Agonist Antagonist
Central
neuronal
(α4)2(β4)3
(α-btox
insesitive)
CNS
Pre & post
junctional
- Pre & post
synaptic
excitation
- Prejunctional
transmitter
release control
↑ed cation
permeability
( Na+ , K+ )
Cytosine,
Epibatidine,
AnatoxinA
Mecamylamine
Erysodine
Lophotoxin
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22. Receptor Location Response Mechanism Agonist Antagonist
Central
neuronal
(α7)5
(α-btox
sensitive)
CNS
Pre & post
junctional
- Pre & post
synaptic
excitation
- Prejunctional
transmitter
release control
↑ed cation
permeability
( Ca++ )
AnatoxinA Methyllycaconitine
α-bungarotoxin
α-conotoxin
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23. MUSCARINIC
ACh
RECEPTORS
(mAChR)
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G- proteins & their specific actions

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Receptor-mediated activation of a G protein and the resultant effector interaction.

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Activation of AC by Gαs

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Activation of PLC by Gαq

28. Receptor Location Cellular Response Functional response Disease relevance
M1
- CNS:
Cortex
Hippocampus
Striatum
Thalamus
- Autonomic ganglia
- Glands
- Enteric nerves
- Couples by Gq/11
- Activates PLC
↑ IP3-DAG → ↑ Ca++, PKC
- Depolarization &
excitation
(↑ EPSP )
- Activates PLD2, PLA2, ↑
AA
- ↑ Cognitive function
- ↑ Seizure activity
- ↓ Dopamine release &
locomotion
- ↑ Depolarization
- ↑ Secretions
- Alzheimer’s
disease
- Cognitive
dysfunction
- Schizophrenia
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29. Receptor Location Cellular Response Functional response Disease relevance
M2
- Thalamus
- Cortex
- Striatum
- Hippocamp
us
- Heart
- Smooth
muscles
- Autonomic
nerve
terminals
- Couples by Gi/G0
- InhibitsAC,
↓ cAMP
- Activation of K+
channels
- Hyperpolarization
& inhibition
Heart :
- SA node:
- Slowed spontaneous
depolarization
- Hyperpolarization
- ↓ HR
- AV node : ↓ conduction
velocity
- Atrium : ↓ contraction, RP
- Ventricle : ↓ contraction
Smooth muscle :
- ↑ Contraction
Peripheral nerves :
- Neural inhibition via auto- &
hetero- receptors
- ↑ ganglionic transmission
CNS :
- Neural inhibition, ↑ tremors,
hypothermia
- Alzheimer’s
disease
- Cognitive
dysfunction
- Pain
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30. Receptor Location Cellular Response Functional response Disease relevance
M3
- Widely in CNS,
- Cortex
- Hippocampus
- Smooth muscles
- Glands
- Heart
- Couples by Gq/11
- Activates PLC
↑ IP3-DAG → ↑ Ca++, PKC
- Depolarization & excitation
(↑ EPSP )
- Activates PLD2, PLA2, ↑ AA
Smooth muscle :
- ↑ contraction
(predominant in bladder)
Glands :
- ↑ Secretion
(salivary gland)
- ↑ food intake, fat, body
weight
- Inhibits DA release
- Synthesis of NO
- COPD
- Urinary
incontinence
- Irritable bowel
disease
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31. Receptor Location Cellular Response Functional response Disease relevance
M4
- CNS (forebrain)
- Striatum
- Cortex
- Hippocampus
- Couples by Gi/G0
- Inhibits AC,
↓ cAMP
- Activation of K+ channels
- Hyperpolarization &
inhibition
Peripheral nerves :
- Neural inhibition via
auto- & hetero- receptors
Analgesia
Catalepsy
↑ DA release
- Parkinson’s disease
- Schizophrenia
- Neuropathic pain
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32. Receptor Location Cellular Response Functional response Disease relevance
M5
Substantia nigra
Low level in CNS &
periphery
Predominant mAChR in
substantia nigra
- Couples by Gq/11
- Activates PLC
↑ IP3-DAG → ↑ Ca++, PKC
- Depolarization & excitation
(↑ EPSP )
- Activates PLD2, PLA2, ↑ AA
- Dilation in cerebral
arteries
- ↑ DA release
- ↑ drug-seeking
behavior & opioids
- Drug dependence
- Parkinson’s disease
- Schizophrenia
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33. References
• Goodman & Gilman’s,The Pharmacological Basis OfTherapeutics, 12th Edition,
McGrawHill Publications, 2011.
• Golan DE, Principles of Pharmacology, 3rd Edition, LippincottWilliams &Wilkins,
Wolters Kluwer, 2012.
• Tripathi KD, Essentials of Medical Pharmacology, 6th Edition, Jaypee Brothers Medical
Publishers, 2010
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