Cholinergic neurotransmission involves the synthesis and the release of acetylcholine (ACh) in order to transmit nerve impulses across the synapse. The process begins with the synthesis of acetyl CoA, a precursor for ACh, from ATP, acetate, and coenzyme A in the mitochondria. Choline, another vital precursor, is transported inside the neuron through choline transporters, including high-affinity choline transporter CHT1, low-affinity choline transporter CTL1, and lower-affinity choline transporter OCT2.
Once inside the neuron, choline and acetyl CoA undergo a reaction catalyzed by an enzyme called choline acetyltransferase (ChAT) to form ACh. The synthesized ACh is actively transported and stored in synaptic vesicles with the help of vesicle-associated transporter (VAT). When electrical impulses reach the axonal terminals, Ca2+ influx occurs within the neuron. Ca2+ binds to synaptotagmin, a calcium-binding site associated with vesicle-associated membrane proteins (VAMP). This binding triggers the fusion of the vesicle membrane with the terminal membrane and facilitates rapid exocytosis of the contents of the vesicles into the synaptic cleft. In the synaptic cleft, ACh binds to and activates cholinergic receptors, namely muscarinic and nicotinic receptors.
The action of ACh is short-lived as it is rapidly hydrolyzed by an enzyme called acetylcholinesterase into acetate and choline. Choline is recycled and taken up by choline transporters in the neuron to undergo another reaction with acetyl CoA. Another enzyme, butyrylcholinesterase or pseudocholinesterase, found in the plasma, liver, intestine, and other tissues, also slowly hydrolyzes ACh.
