H bonding at the helix-bundle crossing controls gating in Kir potassium channels.
Specific stimuli such as intracellular H+ and phosphoinositides (e.g., PIP2) gate inwardly rectifying potassium (Kir) channels by controlling the reversible transition between the closed and open states. This gating mechanism underlies many aspects of Kir channel physiology and pathophysiology; however, its structural basis is not well understood. Here, we demonstrate that H+ and PIP2 use a conserved gating mechanism defined by similar structural changes in the transmembrane (TM) helices and the selectivity filter. Our data support a model in which the gating motion of the TM helices is controlled by an intrasubunit hydrogen bond between TM1 and TM2 at the helix-bundle crossing, and we show that this defines a common gating motif in the Kir channel superfamily. Furthermore, we show that this proposed H-bonding interaction determines Kir channel pH sensitivity, pH and PIP2 gating kinetics, as well as a K+-dependent inactivation process at the selectivity filter and therefore many of the key regulatory mechanisms of Kir channel physiology.
Rapedius
Markus
M
Institute of Physiology II, Friedrich Schiller University, D-07743 Jena, Germany.
Fowler
Philip W
PW
Shang
Lijun
L
Sansom
Mark S P
MS
Tucker
Stephen J
SJ
Baukrowitz
Thomas
T
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D018257:Helix-Loop-Helix Motifs / Q000235:genetics / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008845:Microinjections / Q000379:methods; D008954:Models, Biological; D008958:Models, Molecular; D016296:Mutagenesis / Q000502:physiology; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D011487:Protein Conformation; D051381:Rats; D014981:Xenopus
D019269:Phosphatidylinositol 4,5-Diphosphate; D024661:Potassium Channels, Inwardly Rectifying; D008239:Lysine; D000409:Alanine; D011188:Potassium
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