title: The S1 helix critically regulates the finely tuned gating of Kv11.1 channels.
abstract: Congenital mutations in the cardiac Kv11.1 channel can cause long QT syndrome type 2 (LQTS2), a heart rhythm disorder associated with sudden cardiac death. Mutations act either by reducing protein expression at the membrane and/or by perturbing the intricate gating properties of Kv11.1 channels. A number of clinical LQTS2-associated mutations have been reported in the first transmembrane segment (S1) of Kv11.1 channels, but the role of this region of the channel is largely unexplored. In part, this is due to problems defining the extent of the S1 helix, as a consequence of its low sequence homology with other Kv family members. Here, we used NMR spectroscopy and electrophysiological characterization to show that the S1 of Kv11.1 channels extends seven helical turns, from Pro-405 to Phe-431, and is flanked by unstructured loops. Functional analysis suggests that pre-S1 loop residues His-402 and Tyr-403 play an important role in regulating the kinetics and voltage dependence of channel activation and deactivation. Multiple residues within the S1 helix also play an important role in fine-tuning the voltage dependence of activation, regulating slow deactivation, and modulating C-type inactivation of Kv11.1 channels. Analyses of LQTS2-associated mutations in the pre-S1 loop or S1 helix of Kv11.1 channels demonstrate perturbations to both protein expression and most gating transitions. Thus, S1 region mutations would reduce both the action potential repolarizing current passed by Kv11.1 channels in cardiac myocytes, as well as the current passed in response to premature depolarizations that normally helps protect against the formation of ectopic beats.
authors.affiliation: From the Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010.|the St. Vincent's Clinical School, University of New South Wales, New South Wales 2052, and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Phan
authors.affiliation: From the Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010.|the St. Vincent's Clinical School, University of New South Wales, New South Wales 2052, and.
authors.forename: Chai Ann
authors.initials: CA
authors.lastname: Ng
authors.affiliation: From the Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010.
authors.forename: Erikka
authors.initials: E
authors.lastname: David
authors.affiliation: the School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Shishmarev
authors.affiliation: the School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kuchel
authors.affiliation: From the Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010.|the St. Vincent's Clinical School, University of New South Wales, New South Wales 2052, and.
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
authors.affiliation: From the Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010, m.perry@victorchang.edu.au.|the St. Vincent's Clinical School, University of New South Wales, New South Wales 2052, and.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Perry
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000072237:ERG1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism*; D017433:Protein Structure, Secondary; D014982:Xenopus laevis
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human
keywords: biophysics; cardiovascular disease; channel activation; electrophysiology; hERG; ion channel; mutagenesis in vitro; nuclear magnetic resonance (NMR); oocyte; potassium channel