5.6: Cholinergic Receptors: Nicotinic

Nicotinic receptors are ligand-gated ion channels that are activated by acetylcholine and nicotine. Upon activation, they cause a rapid increase in the permeability of cells to K⁺, Na⁺, and Ca²⁺, followed by depolarization and excitation. They are in the autonomic ganglia, skeletal neuromuscular junction, CNS, and adrenal medulla.

There are two types of nicotinic receptors: neuromuscular (N_M/NM/N₁) and neuronal (N_N/NN/N₂). The two families differ based on their location and selectivity to agonists and antagonists. The neuromuscular junction possesses the N_M type, whereas the CNS, PNS, and non-neuronal tissues have the N_N type. D-tubocurarine, succinylcholine, and decamethonium block the N_M receptors, while trimethaphan and hexamethonium block the N_N receptors.

Nicotinic receptors have pentameric subunits (α, β, γ, ε, and δ) that form a rosette-like receptor complex. N_M receptors have α2, β, γ (or ε), and δ subunits, while N_N receptors have only α or α, β subunits. Each subunit has an intracellular C-terminus, an extracellular N-terminus, and four α helical transmembrane domains around a central pore that serves as the ion channel. On the extracellular domain of the receptors, two acetylcholine binding sites exist at the αγ and αδ interfaces.

Acetylcholine binding to nicotinic receptors causes a change in cell membrane permeability, allowing cation movement through the ion channel. Cation flux depolarizes the end plate, resulting in the contraction of muscles at the neuromuscular junction or nerve impulse continuation at the autonomic ganglia.

nAChRs are ligand-gated ion channels having a higher affinity for nicotine than ACh or  muscarine.

They are classified into N_M, or muscle type and N_N, or neuronal type.

N_M receptors are present at the neuromuscular junction, while N_N receptors are present in the autonomic ganglia and the adrenal medulla.

Structurally, nicotinic receptors are rosette-shaped pentamers having a central pore. The pore serves as the ion channel. On the extracellular domain of the receptor, two ACh binding sites are present.

N_M receptors comprise alpha, beta, gamma, and delta subunits, whereas N_N receptors are composed of only alpha and beta subunits.

Ligand binding to the receptor opens the ion channel to cations such as sodium ions, potassium ions, and calcium ions.

Ion influx depolarizes the end plate, causing either muscle contraction at the neuromuscular junction or nerve impulse continuation at the autonomic ganglia.