Cholinergic transmission dr jayesh vaghela

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CHOLINERGIC TRANSMISSION

&RECEPTOR

PHARMACOLOGY

Dr. Jayesh Vaghela

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CHOLINERGIC TRANSMISSION

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Choline Acetyl Transferase ( ChAT )

• Catalyzes the final step in the synthesis of Achi.e.- Acetylation of Choline with Acetyl CoA

• Acetyl CoA ⇒ from pyruvate via pyruvate dehydrogenasereaction- In mitochondria at axonal terminals

• Choline ⇒ Reuptake after release

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Perikaryon ChAT

Axonal Terminal Acetyl CoA Choline

Cytoplasm ACh

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Choline & Its Transport• Choline: - Available from diet

- Essential for normal function of cells- Structural integrity- Signaling functions of cell membranes

• 2 Transport Mechanisms- Na+ independent transport system- Na+ & Cl- dependent transport systemPredominant,

Provide Choline forAch synthesis

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Choline Transporter [ CHT 1 ]• Homologous to Na+ dependent glucose transport family• Location: - Intracellular vesicular structures

- Co-localizes with,- VAMP2 – Vesicle-associated membrane protein- VAChT - Vesicular ACh Transporter

• During transmitter release events ⇒ ↑ed Trafficking 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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Storage of ACh• Synthesis of ACh in cytoplasm• Transported into synaptic vesicles by VAChT 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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• 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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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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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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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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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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Characteristic Acetylcholinesterase ( True )

Butyrylcholinesterase ( Pseudo )

Distribution - All cholinergic sites- RBCs- Gray matter

- Plasma- Liver- Intestine- White matter

Hydrolysis of-- ACh- Methacholine- Benzoylcholi

ne- Butyrylcholin

e

- 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 of ACh action

Hydrolysis of ingested esters

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NICOTINICACh

RECEPTORS( nAChR )

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Receptor Location Response Mechanism Agonist Antagonist

Skeletal muscleNM

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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Receptor Location Response Mechanism Agonist AntagonistPeripheral neuronalNN

(α3)2(β4)3

Autonomic gangliaAdrenal medulla

Excitatory:

Depolarization:Firing of postganglionic neuron;

Secretion of catecholamines


ACh

Nicotine

Epibatidine

Trimetharphan

Mecamylamine

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Receptor Location Response Mechanism Agonist AntagonistCentral neuronal

(α4)2(β4)3(α-btox insesitive)

CNS

Pre & post junctional

- Pre & post synaptic excitation

- Prejunctional transmitter release control


Cytosine,

Epibatidine,

Anatoxin A

Mecamylamine

Erysodine

Lophotoxin

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Receptor

Location Response Mechanism Agonist Antagonist

Central neuronal

(α7)5(α-btoxsensitive)

CNSPre & post junctional

- Pre & post synaptic excitation

- Prejunctional transmitter release control

↑ed cation permeability( Ca++ )

Anatoxin A Methyllycaconitine

α-bungarotoxin

α-conotoxin

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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

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Receptor Location Cellular Response Functional

responseDisease

relevance

M1

- CNS:CortexHippocampusStriatumThalamus

- 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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Receptor Location Cellular

Response Functional response Disease relevance

M2

- Thalamus- Cortex- Striatum- Hippocam

pus- Heart- Smooth

muscles- Autonomi

c nerve terminals

- Couples by Gi/G0

- Inhibits AC,↓ cAMP- Activation of K+

channels- Hyperpolarizati

on & inhibition

Heart :- SA node:

- Slowed spontaneous

depolarization- Hyperpolarization- ↓ HR

- AV node : ↓ conduction velocity

- Atrium : ↓ contraction, RP

- Ventricle : ↓ contractionSmooth muscle :- ↑ ContractionPeripheral nerves :- Neural inhibition via

auto- & hetero- receptors

- ↑ ganglionic transmission

CNS :- Neural inhibition, ↑ tremors, hypothermia

- Alzheimer’s disease

- Cognitive dysfunction

- Pain

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Receptor Location Cellular Response Functional response Disease

relevance

M3

- Widely in CNS,

- Cortex

- Hippocampus

- Smooth muscles

- Glands

- Heart

- Couples by Gq/11



(↑ EPSP )


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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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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Receptor Location Cellular Response Functional

responseDisease

relevance

M5

Substantia nigra

Low level in CNS & periphery

Predominant mAChR in substantia nigra

- Couples by Gq/11



(↑ EPSP )


- Dilation in cerebral arteries

- ↑ DA release

- ↑ drug-seeking behavior & opioids

- Drug dependence

- Parkinson’s disease

- Schizophrenia

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References

• Goodman & Gilman’s, The Pharmacological Basis Of Therapeutics, 12th Edition, McGrawHill Publications, 2011.

• Golan DE, Principles of Pharmacology, 3rd Edition, Lippincott Williams & Wilkins, Wolters Kluwer, 2012.

• Tripathi KD, Essentials of Medical Pharmacology, 6th Edition, Jaypee Brothers Medical Publishers, 2010

Cholinergic transmission dr jayesh vaghela

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