acetylcholine

Acetylcholine (ACh) is a neurotransmitter used by neurons in both the peripheral and central nervous systems. It is a quaternary ammonium compound, highly polar, and does not cross the blood-brain barrier easily, so central effects arise from neurons that synthesize and release it directly within the brain.

ACh is synthesized in cholinergic neurons from choline and acetyl-CoA by the enzyme choline acetyltransferase (ChAT). It is stored in synaptic vesicles and released into the synaptic cleft in a calcium-dependent manner when an action potential arrives. In the synapse, acetylcholine is rapidly hydrolyzed by acetylcholinesterase (AChE) into acetate and choline; choline is reabsorbed by a transporter to enable resynthesis and reuse of ACh.

ACh acts on two main receptor families: nicotinic receptors (ionotropic) and muscarinic receptors (metabotropic). Nicotinic receptors are found at skeletal muscle neuromuscular junctions and in autonomic ganglia, while muscarinic receptors are widespread in the brain and peripheral organs. Pharmacological agents that target these receptors or AChE can modulate cholinergic signaling, producing characteristic physiological effects.

In the peripheral nervous system, ACh mediates skeletal muscle contraction at the neuromuscular junction and modulates heart rate, glandular activity, and other autonomic responses. In the central nervous system, cholinergic neurons in the basal forebrain and septohippocampal pathway contribute to learning, memory, arousal, and attention.

Clinically, cholinergic signaling is implicated in disorders such as myasthenia gravis (antibodies against nicotinic receptors) and Alzheimer’s disease (loss of cholinergic neurons). Organophosphate and nerve-agent exposure inhibit AChE, causing excessive ACh activity; treatment includes AChE inhibitors and receptor-targeted therapies as appropriate.