ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are members a superfamily of pentameric ligand (neurotransmitter)-gated ion channels (pLGICs), which play a central role in information processing in the brain. The muscle-type nAChR is exquisitely sensitive to its lipid environment. In the absence of activating cholesterol and anionic lipids, the nAChR adopts a conformation where agonist binding is uncoupled from channel gating. Lipids likely influence the coupling of binding and gating via the outermost lipid-exposed transmembrane α-helix, M4 (one per subunit), which extends beyond the bilayer to interact with key structures at the interface between the agonist binding and transmembrane gating domains. The nAChR M4 is also the site of both point and truncation mutations that lead to altered neuromuscular communication (congenital myasthenic syndromes), while an M4 truncation mutation in the GABAA receptor leads to genetic epilepsy syndrome. In this seminar, we explore the mechanisms by which changes in this peripheral transmembrane α-helix, M4, are allosterically communicated to key structures that influence channel gating and thus how M4 acts as an intrinsic regulator of pLGIC function in both normal and diseased states.
BIO: Dr. Baenziger obtained his Ph.D. working at the National Research Council of Canada with Dr. Ian C.P. Smith, a pioneer in the use of solid state NMR methods to study biological molecules and human disease. Dr. Baenziger completed his doctoral studies in Biochemistry at the University of Ottawa in 1989, and then undertook a postdoctoral fellowship jointly at Harvard Medical School and Boston University where he began working on the structural and functional characterization of pentameric ligand-gated ion channels (pLGICs). In 1992, Dr. Baenziger joined the Department of Biochemistry at the University of Ottawa. He is currently the President of the Biophysical Society of Canada and serves on the executive of the International Union of Pure and Applied Biophysics.