Ion conduction in Cys-loop receptors: beyond TM2

Tim Hales (Ninewells Hospital & Medical School, University of Dundee, UK)

Abstract:5-hydroxytryptamine-type3 (5-HT3) and nicotinic acetylcholine (nACh) receptors are cation-selective ion channels of the Cys-loop superfamily of ligand-gated ion channels that also includes the anion selective gamma-aminobutyric acid typeA (GABAA) and strychnine-sensitive glycine receptors. Multiple lines of evidence indicate that the transmembrane pore of such receptors is formed by the alpha-helical second transmembrane (TM2) domain and flanking sequences contributed by each of the subunits present within the pentameric receptor complex. Well defined amino acid residues at loci within, and adjacent to, the TM2 domain influence single channel conductance, ion selectivity, and other aspects of receptor function that include gating and desensitization. However, more recent work has identified important structural determinants of single channel conductance and ion selectivity that are not associated with the TM2 domain. Direct experimental evidence indicates that the intracellular domain of Cys-loop receptors, in particular a region of the loop linking TM3 and TM4 termed the membrane associated (MA)-stretch, exerts a strong influence upon ion channel biophysics and a structural basis of this influence has been proposed. This presentation will explore how our knowledge of ion conduction and selectivity in Cys-loop receptors has evolved beyond TM2.