Function of Acetylcholinesterase in Synapses
Acetylcholinesterase (AChE) terminates nerve impulse transmission at cholinergic synapses by rapidly hydrolyzing the neurotransmitter acetylcholine into acetate and choline, preventing continuous postsynaptic receptor stimulation. 1
Primary Enzymatic Function
AChE's essential role is to clear acetylcholine from the synaptic cleft immediately after neurotransmission, ensuring that nerve signals are discrete rather than continuous. 2, 3
- The enzyme breaks down acetylcholine molecules through hydrolysis, producing acetate and choline as products 1, 4
- This catalytic activity occurs at the bottom of a deep, narrow active-site gorge within the enzyme's structure 4, 3
- AChE is one of nature's most efficient enzymes, with an extraordinarily high turnover rate that matches its biological requirement for rapid neurotransmitter clearance 3
Clinical Significance: What Happens When AChE is Blocked
The critical importance of AChE becomes evident when its function is inhibited by organophosphates or nerve agents:
- Blockade of AChE hydrolysis causes rapid acetylcholine accumulation within the synaptic cleft at both muscarinic and nicotinic receptors, leading to intense postsynaptic cholinergic overstimulation 1
- At nicotinic receptors (skeletal muscle and autonomic ganglia), acetylcholine accumulation generates involuntary muscle contractions followed by complete depolarization block and flaccid paralysis 1, 5
- At muscarinic receptors (smooth muscle, cardiac muscle, secretory glands), excess acetylcholine causes bronchospasm, bradycardia, excessive secretions, and gastrointestinal hypermotility 1, 6
- In the central nervous system, acetylcholine accumulation produces anxiety, disorientation, seizures, and coma, potentially progressing to respiratory arrest within seconds 1
Structural Mechanism
- The active site is sequestered at the bottom of a deep gorge, with a peripheral anionic site at the gorge entrance 2, 7
- Substrate and product traffic occurs through this confined space, with acetylcholine binding at the peripheral site before reaching the catalytic site 7
- Multiple exit pathways exist for products, including routes along the gorge axis and through "back-door" and "side-door" channels 4
Synaptic Stability Function
Beyond its classical enzymatic role, AChE is crucial for maintaining the structural stability of neuromuscular synapses, as acetylcholine receptor clusters at neuromuscular junctions initially assemble but fail to maintain stability in AChE's absence 8
Common Pitfall
The American Society of Anesthesiologists emphasizes that measuring AChE activity in red blood cells approximates central nervous system AChE activity and roughly indicates the degree of toxicity in organophosphate poisoning, making it a useful clinical marker when direct measurement of nerve agents is unavailable 1