Acetylcholine (ACh) is a neurotransmitter that plays a crucial role in the central and peripheral nervous systems. It is involved in various physiological processes, including muscle contraction, regulation of heart rate, and modulation of cognitive functions.

In this article, brace yourself to learn about the biosynthesis of acetylcholine, its receptors, antagonists and other relevant topics.

BIOSYNTHESIS OF ACETYLCHOLINE

The biosynthesis of acetylcholine occurs within cholinergic neurons and involves several enzymatic steps. The primary precursor for acetylcholine synthesis is choline, which is obtained from the diet or synthesized de novo in the liver. Choline is transported into cholinergic nerve terminals via a high-affinity, sodium-dependent choline transporter.

Once inside the nerve terminal, choline acetyltransferase (ChAT), an enzyme located in the cytoplasm, catalyzes the transfer of an acetyl group from acetyl coenzyme A (acetyl-CoA) to choline, forming acetylcholine and coenzyme A (CoA). This reaction takes place in the presynaptic terminal of cholinergic neurons and represents the final step in acetylcholine biosynthesis.

After its synthesis, acetylcholine is stored in synaptic vesicles within the nerve terminal. Upon neuronal depolarization, these vesicles undergo exocytosis, releasing acetylcholine into the synaptic cleft. Once in the synaptic cleft, acetylcholine binds to its receptors on the postsynaptic membrane, eliciting various physiological responses.

ACETYLCHOLINE RECEPTORS

Acetylcholine exerts its effects by binding to two main types of receptors: nicotinic and muscarinic receptors. Nicotinic receptors are ligand-gated ion channels, while muscarinic receptors belong to the G protein-coupled receptor (GPCR) family.

1). Nicotinic receptors

Nicotinic receptors are pentameric structures composed of five subunits that form a central ion channel. These receptors are activated by the binding of acetylcholine, leading to the influx of cations such as sodium and calcium into the postsynaptic cell. Nicotinic receptors are found at neuromuscular junctions, where their activation leads to muscle contraction. Additionally, they are present in the autonomic ganglia and the central nervous system, where they modulate synaptic transmission.

2). Muscarinic receptors

Muscarinic receptors are GPCRs that are coupled to intracellular signaling pathways through heterotrimeric G proteins. There are five subtypes of muscarinic receptors (M1–M5), each with distinct tissue distributions and signaling properties. Upon acetylcholine binding, muscarinic receptors can activate or inhibit various intracellular signaling cascades, leading to diverse physiological responses. Muscarinic receptors are widely distributed in the central and peripheral nervous systems and are involved in regulating heart rate, smooth muscle contraction, glandular secretion, and cognitive functions.

ACETYLCHOLINE ANTAGONISTS

Antagonists of acetylcholine receptors are pharmacological agents that block the binding of acetylcholine to its receptors, thereby inhibiting its physiological effects. These antagonists can be classified based on their selectivity for nicotinic or muscarinic receptors.

A). Nicotinic antagonists: Nicotinic receptor antagonists can be further divided into two subtypes: neuromuscular blockers and ganglionic blockers.

B). Neuromuscular blockers: Neuromuscular blockers are drugs that act at the neuromuscular junction to block nicotinic receptors, leading to muscle paralysis. These agents are used during surgical procedures to facilitate endotracheal intubation and to induce muscle relaxation. Examples of neuromuscular blockers include tubocurarine, vecuronium, rocuronium, and succinylcholine.

C). Ganglionic blockers: Ganglionic blockers interfere with nicotinic receptors in autonomic ganglia, thereby disrupting sympathetic and parasympathetic transmission. These agents were historically used to treat hypertension but have largely been replaced by more selective antihypertensive drugs. Examples of ganglionic blockers include hexamethonium and mecamylamine.

D). Muscarinic antagonists: Muscarinic receptor antagonists, also known as anticholinergics, block the effects of acetylcholine at muscarinic receptors. These agents have a broad range of clinical applications due to their ability to inhibit parasympathetic functions.

E). Atropine: Atropine is a prototypical muscarinic antagonist derived from the plant Atropa belladonna. It has widespread clinical use as an antidote for organophosphate poisoning, a premedication for anesthesia to reduce salivary and bronchial secretions, and as a mydriatic agent to dilate the pupil during ophthalmic examinations.

F). Scopolamine: Scopolamine is another muscarinic antagonist that is used to prevent motion sickness and nausea. It is also employed as a preanesthetic medication and has been investigated for its potential cognitive-enhancing effects.

G). Antimuscarinic agents for veractive bladder: Several muscarinic antagonists are used to treat overactive bladder (OAB) by reducing detrusor muscle contractions and increasing bladder capacity. Examples of these agents include oxybutynin, tolterodine, solifenacin, darifenacin, and fesoterodine.

In conclusion, acetylcholine is a pivotal neurotransmitter involved in numerous physiological processes through its actions at nicotinic and muscarinic receptors. The biosynthesis of acetylcholine involves the enzymatic conversion of choline and acetyl-CoA by ChAT within cholinergic neurons. Acetylcholine exerts its effects by binding to nicotinic and muscarinic receptors, which mediate diverse physiological responses. Antagonists of acetylcholine receptors, including nicotinic and muscarinic antagonists, have important clinical applications in various medical fields.

Understanding the biosynthesis and pharmacology of acetylcholine and its antagonists is crucial for developing therapeutic strategies for conditions involving dysregulation of cholinergic neurotransmission.