NAChR

Neuronal nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels in the nervous system that respond to acetylcholine and nicotine. They belong to the Cys-loop superfamily of ligand-gated ion channels. Activation by acetylcholine opens the channel pore, allowing cations such as Na+ and Ca2+ to enter and K+ to exit, producing rapid depolarization and modulating neurotransmitter release. In the brain, nAChRs influence synaptic transmission and contribute to processes such as attention, learning, and reward.

Subunit composition determines receptor properties. Vertebrate nAChRs are assembled from alpha (α2–α10) and beta (β2–β4) subunits, with the exact makeup shaping agonist affinity, calcium permeability, and desensitization kinetics. Common neuronal subtypes include heteromeric α4β2 and α3β4 receptors, and the homomeric α7 receptor. Many native receptors also incorporate auxiliary subunits such as α5 or β3, which modify pharmacology and function. The α7 receptor, in particular, is highly permeable to Ca2+, which has important signaling implications.

Distribution and function: nAChRs are widely expressed in the cortex, hippocampus, thalamus, and other brain regions, as well as in autonomic ganglia. Presynaptic nAChRs can regulate the release of dopamine, GABA, glutamate, and other transmitters, linking cholinergic signaling to broader circuit activity. Nicotinic signaling can influence cognitive processes and plasticity, and dysregulation of nAChRs has been associated with nicotine addiction and several CNS disorders.

Clinical and pharmacology: Drugs targeting nAChRs include nicotine and varenicline, a partial agonist at α4β2 receptors, used for smoking cessation. Mecamylamine is a nonselective antagonist. Selective α7 agonists and α4β2 modulators are under investigation for cognitive impairment and neurodegenerative diseases. Genetic variations in nAChR subunits have been linked to nicotine dependence and risk for certain neurological and psychiatric conditions.