Pore-opening mechanism of the nicotinic acetylcholine receptor evinced by proton transfer.
The conformational changes underlying cysteine-loop receptor channel gating remain elusive and controversial. We previously developed a single-channel electrophysiological method that allows structural inferences about the transient open-channel conformation to be made from the effect and properties of introduced charges on systematically engineered ionizable amino acids. Here we have applied this methodology to the entire M1 and M3 segments of the muscle nicotinic acetylcholine receptor, two transmembrane alpha-helices that pack against the pore-lining M2 alpha-helix. Together with our previous results on M2, these data suggest that the pore dilation that underlies channel opening involves only a subtle rearrangement of these three transmembrane helices. Such a limited conformational change seems optimal to allow rapid closed-open interconversion rates, and hence a fast postsynaptic response upon neurotransmitter binding. Thus, this receptor-channel seems to have evolved to take full advantage of the steep dependence of ion- and water-conduction rates on pore diameter that is characteristic of model hydrophobic nanopores.
Cymes
Gisela D
GD
Department of Molecular and Integrative Physiology, Center for Biophysics and Computational Biology and Neuroscience Program, University of Illinois at Urbana-Champaign, 407 South Goodwin Avenue, 524 Burrill Hall, Urbana, Illinois 61801, USA.
Grosman
Claudio
C
D000595:Amino Acid Sequence; D002460:Cell Line; D006801:Humans; D015640:Ion Channel Gating; D017136:Ion Transport; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011522:Protons; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D017386:Sequence Homology, Amino Acid
D011522:Protons; D011978:Receptors, Nicotinic