How does acetylcholine formation and release occur at the neuromuscular junction and what are the effects of drugs that enhance or block transmission?

Acetylcholine Formation and Release at the Neuromuscular Junction

Acetylcholine formation and release at the neuromuscular junction involves vesicle formation, acetylcholine synthesis, calcium-mediated exocytosis, and vesicle recycling, while various drugs can enhance or block this transmission through acetylcholine-like actions or by inactivating acetylcholinesterase.

Process of Acetylcholine Formation and Release

Vesicle Formation and Transport

• Small vesicles (approximately 40 nm) are formed by the Golgi apparatus in the motoneuron cell body in the spinal cord 1
• These vesicles are transported via axoplasmic streaming through the axon to the neuromuscular junction 2
• Approximately 300,000 vesicles collect at a single skeletal muscle end plate 1

Acetylcholine Synthesis and Storage

• Acetylcholine is synthesized in the cytosol of the nerve terminal and immediately transported into vesicles 2
• Each vesicle stores about 10,000 molecules of acetylcholine in highly concentrated form 1
• The acetylcholine comes from the same pool of transmitter that is liberated by nerve impulses 1

Release Mechanism

• When an action potential arrives at the nerve terminal, it opens voltage-gated calcium channels 2
• Calcium concentration inside the terminal increases approximately 100-fold 1
• This calcium influx increases vesicle fusion with the terminal membrane about 10,000-fold 2
• Approximately 125 vesicles rupture with each action potential, releasing acetylcholine into the synaptic space 1

Acetylcholine Recycling

• After release, acetylcholine is rapidly broken down by acetylcholinesterase into acetate ion and choline 2
• Choline is actively reabsorbed into the nerve terminal to be reused for new acetylcholine synthesis 1
• This entire sequence occurs within 5-10 milliseconds 2

Vesicle Recycling

• New vesicles form within seconds after each action potential 1
• Coated pits appear in the terminal membrane due to contractile proteins, especially clathrin 2
• Within approximately 20 seconds, these pits break away to form new vesicles 1
• Acetylcholine is transported into these new vesicles within seconds, making them ready for another release cycle 2

Drugs Affecting Neuromuscular Junction Transmission

Drugs That Mimic Acetylcholine

• Compounds like methacholine, carbachol, and nicotine have similar effects to acetylcholine on muscle fibers 1
• Unlike acetylcholine, these drugs are either not destroyed by cholinesterase or are destroyed very slowly 2
• They cause localized depolarization at the motor end plate, leading to repeated action potentials and muscle spasm 1

Drugs That Inactivate Acetylcholinesterase

• Neostigmine, physostigmine, and diisopropyl fluorophosphate inactivate acetylcholinesterase in synapses 2
• This inactivation prevents the breakdown of acetylcholine, causing it to accumulate with successive nerve impulses 1
• Neostigmine and physostigmine temporarily inactivate acetylcholinesterase for several hours 2
• Diisopropyl fluorophosphate (a nerve gas) inactivates acetylcholinesterase for weeks, making it particularly lethal 1
• These drugs can cause muscle spasm and potentially fatal laryngeal spasm 2

Development of the Neuromuscular Junction

• During development, acetylcholine receptors initially appear diffusely distributed on embryonic myotubes 3
• They later become highly concentrated (approximately 10,000 per μm²) in the postsynaptic membrane 4
• Rapsyn, a peripheral membrane protein, is essential for the formation of acetylcholine receptor clusters 4
• The neuromuscular junction acquires its essential components early in development, with acetylcholine release capability and functional receptors appearing independently 5