Nicotinic acetylcholine receptors, or nAChRs, are neuron receptor proteins that signal for muscular contraction upon a chemical stimulus. They are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the presynaptic and postsynaptic sides of the neuromuscular junction.

Neuroreceptors are central players in synaptic transmission, receiving and interpreting chemical signals between neurons in the nervous system. Neuroreceptors of the ligand-gated ion channel (LGIC) family directly convert incoming chemical signals into electrical output. In the LGIC gating process, neurotransmitters are recognized by ligand-binding domains, and binding triggers conformational changes within the structure to form an ion-conducting pore.

nAChRs are a prototypical member of the cys-loop receptor family. These pentameric ligand-gated ion channels share a conserved molecular architecture with other members in the family. nAChRs are fast-activating cation-selective receptors that are activated by the neurotransmitter acetylcholine and mediate excitatory neurotransmission. In addition, they also play diverse roles in muscle contraction, cognition, nociception, aging and addiction, thereby acting as pharmacological and therapeutic targets for several pathological conditions.

The nAChRs is a cylindrical transmembrane glycoprotein, having five homologous subunits embedded longitudinally in the cell membrane with its long axis perpendicular to the membrane plane. The individual subunits are arranged in a ring, forming a pseudo-fivefold symmetric assembly that is 160Å long and up to 80 Å in diameter. Each AChR subunit is partitioned into the following three structural components: a large N-terminal hydrophilic extracellular domain (ECD), a transmembrane domain (TMD) comprising four hydrophobic segments and a hydrophilic cytoplasmic intracellular domain (ICD) of variable size and amino acid sequence.

The extracellular domain

In each subunit, the ECD of AChRs is organized into a β-sandwich core having a unique immunoglobulin-like topology, stabilized by inner hydrophobic residues. Each subunit is comprised of 10 β-strands: β1, β2, β3, β5, β6 and β8 form the inner sheet whereas β4, β7, β9 and β10 form the outer sheet, with interconnecting loops and a three-turn N-terminal α-helix. The ECD not only provide an interface for the agonist binding site comprising several conserved residues, but also bear putative sites for glycosylation. Early mutagenesis and affinity labelling studies have revealed that the ECD of the neuromuscular AChR contains two main differentiated regions that form the agonist binding site: the ‘principal’ component (also known as plus side) and the ‘complementary’ component (or the minus side). The principal side is completely formed by the α-subunit, embedding several aromatic residues together with a cysteine pair at 192-193, in three loop-forming domains called loops A, B and C. The complementary side is formed of the adjacent non α-subunit (γ/ε or δ) involving loops D, E and F.

The transmembrane domain

The TMD of each AChR subunit is composed of four membrane-spanning α-helices, M1-M4. M2 α-helices from all subunits line the ion-conducting pore. These pore-lining M2 helices form the inner ring which is flanked mostly by polar or negatively-charged amino acids. Mutations of these charged residues result in alteration in the channel conductance. The segments M1, M3 and M4 cluster together to form an outer ring, protecting the inner ring of the M2 domain. The TMD interacts with the lipid bilayer and is also known to play modulating roles in ion permeation pathway as revealed by various X-ray structures.

The intracellular domain

The intracellular region of AChR consists largely of a cytoplasmic domain connecting the carboxy-terminus of M3 to the amino-terminus of M4. It is mostly α-helical and of variable length and amino acid sequence. It plays important roles in protein-protein interactions involving receptor assembly, trafficking and sub-cellular localization and also in protein modulation. In addition, it has been recently shown that ICD of a member of cys loop receptor family also contributes toward ion permeation properties.


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