nAChRs

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that mediate fast synaptic transmission in the nervous system and at the neuromuscular junction. They are activated by acetylcholine and nicotine, and open cation-permeable channels allowing Na+ and Ca2+ influx with K+ efflux, causing depolarization.

Subunit composition determines receptor properties. Muscle-type nAChRs in adults typically have two α1 subunits and β1, δ, and ε (or γ in fetal tissue). Neuronal nAChRs are more diverse, including α4β2 and α7 (often homomeric), among others.

Function and signaling: Upon binding acetylcholine, the receptor undergoes a conformational change that opens the pore, producing fast excitatory currents. The α7 subtype is particularly permeable to Ca2+ and can influence intracellular signaling and gene expression. Receptors desensitize with sustained agonist exposure.

Distribution and roles: Muscle-type receptors mediate neuromuscular transmission. In the brain, nAChRs modulate neurotransmitter release, synaptic plasticity, and cognitive processes, and participate in reward pathways relevant to nicotine addiction.

Pharmacology and clinical relevance: Nicotinic receptors are targets of drugs such as nicotine, varenicline (a partial α4β2 agonist), and cytisine. Antagonists include mecamylamine and d-tubocurarine. Autoimmune antibodies against nAChRs cause myasthenia gravis; neuronal receptor dysfunction is linked to several neurological disorders.

Structure: Each receptor comprises five subunits arranged around a central pore. Subunits contribute an extracellular ligand-binding domain and four transmembrane segments (M1–M4). The ligand-binding sites lie at subunit interfaces, and pore opening permits cation entry, with Ca2+ influx notable in α7 receptors.