Learning Objective

Describe the synthesis, storage, release, and termination of ACh, and identify major drug targets that modify cholinergic transmission.

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Key Steps in Cholinergic Transmission

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Choline Uptake ➀

• Choline is transported into the presynaptic terminal by a Na-dependent active transporter.
• Hemicholinium inhibits this transporter → ↓ ACh synthesis.

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ACh Synthesis & Vesicular Storage

• ACh is synthesized from choline + acetyl-CoA via choline acetyltransferase (ChAT).
• ACh is then packaged into synaptic vesicles.

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Vesicle Fusion & Release (Blocked by Botulinum Toxin – ➁

• Depolarization of the presynaptic membrane opens voltage-gated Ca²⁺ channels.
• Ca²⁺ influx triggers vesicle fusion (via SNARE proteins, including synaptobrevin) → ACh exocytosis.
• Botulinum toxin cleaves SNARE proteins → prevents ACh release.

Clinical Uses of Botulinum Toxin:

Blepharospasm, strabismus, hyperhidrosis, dystonia, cosmetic procedures, overactive bladder, and migraine prevention.

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Presynaptic Autoreceptors

• Cholinergic terminals contain Gi-coupled autoreceptors.
• Activation → ↓ ACh release (negative feedback).

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Postjunctional Receptors (Nicotinic & Muscarinic – ➃

• ACh activates N (nicotinic) and M (muscarinic) receptors.
• These are major drug targets for agonists (direct-acting cholinomimetics) and antagonists.

Muscarinic receptor actions:

• ↓ HR
• ↑ secretions
• ↑ smooth muscle contraction
  (M-receptor agonists and antagonists are non-specific.)

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Termination of Action: Acetylcholinesterase (AChE)

• AChE rapidly breaks down ACh in the synaptic cleft.
• This is the main mechanism for stopping ACh signaling.

AChE Inhibitors – ➂:

• Reversible: edrophonium, physostigmine, neostigmine
• Irreversible: organophosphates such as malathion, parathion
• AChE inhibitors only work at innervated cholinergic terminals, where ACh is released.

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Summary Table – Drug Targets at the Cholinergic Junction