The nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel protein that mediates fast excitatory synaptic transmission in the peripheral and central nervous systems. Changes in the structure and function of the nAChR can lead to serious impairment of physiological processes. Mutations in the lipid-protein interface of the nAChR can cause alterations in the gating machinery of the nAChR. Indeed, the cholesterol-sensitive nAChR mutant αC418W located in the αM4 domain, causes slow-channel congenital myasthenic syndrome. Therefore, my particular interests is to better understand the role of the lipid-protein interface of the nAChR in the βM4 transmembrane domain.

In this study, we combined site-directed mutagenesis, radioligand binding assays, electrophysiological recordings, and Fourier analyses to characterize the functional role and structural aspects of the bM4 transmembrane domain of the Torpedo californica nAChR.

Resent results demonstrates that the βM4 domain plays a more structural role during nAChR channel activation. βM4 displays a larger number of non-functional mutants and a lower change in the periodicity value as compared to αM4 and γM4 suggesting a more “tightly-packed” and rigid-body domain compared to other transmembrane domains.