Gating of nicotinic ACh receptors; new insights into structural transitions triggered by agonist binding that induce channel opening

Abstract

Nicotinic acetylcholine receptors (nAChRs) are in the superfamily of Cys-loop ligand-gated ion channels, and are pentameric assemblies of five subunits, with each subunit arranged around the central ion-conducting pore. The binding of ACh to the extracellular interface between two subunits induces channel opening. With the recent 4 A resolution of the Torpedo nAChR, and the crystal structure of the related molluscan ACh binding protein, much has been learned about the structure of the ligand binding domain and the channel pore, as well as major structural rearrangements that may confer channel opening. For example, the putative pathway coupling agonist binding to channel gating may include a major rearrangement of the C-loop within the ligand binding pocket, and the disruption of a salt bridge between an arginine residue at the end of the beta10 strand and a glutamate residue in the beta1-beta2 linker. Here we will review and discuss the latest structural findings aiming to further refine the transduction pathway linking binding to gating for the nAChR channels, and discuss similarities and differences among the different members of this Cys-loop superfamily of receptors.

Figure 1

Ribbon diagrams of two subunits of the Torpedo nAChR (PDB:2BG9) A, the α helicies are shown in red and the β strands in blue. The extracellular ligand binding domain (LBD) and transmembrane domains are highlighted. B, two major structural elements of the LBD are shown: the transmitter binding site and the transition zone. The transmitter binding site is composed of a cluster of aromatic residues from both the principal and complimentary subunits and is capped by the C-loop. The transition domain consists of several loops including: Cys-loop, β1–β2 linker, β8–β9 linker, β10–M1 linker and the M2–M3 linker. These loops are involved in converting structural changes at the transmitter binding site down to the pore domain and inducing channel gating.

Figure 2

Possible movements within the ligand binding domain upon agonist binding A, the closed receptor state (Torpedo nAChR α subunit; PDB:2BG9) is in red and a possible active or desensitized receptor state (Lymnaea AChBP bound to carbamylcholine; PDB:1UV6) for the LBD is in grey. Boxes indicate areas that are expanded in B–D. B, upon agonist binding, the C-loop moves in toward the channel, bringing Y185 and K139 (AChBP) into close contact, breaking a previous interaction between K139 and D194 (not shown). C, movement of the β1–β2 linker and the β10–M1 linker leads to the disruption of a salt-bridge between E45 and R209 (Torpedo nAChR), allowing for the possible isomerization of P272 (Torpedo nAChR) in some Cys-loop receptors. In addition, the Cys-loop may shift position in the presence of agonist. D, the β8–β9 linker also is thought to shift in a clockwise direction. These cartoons are derived from overlays of current crystal structures and while these are suggested movements based on agonist binding to the nAChR, some of these changes could be species related.