title: Gating of inward-rectifier K+ channels by intracellular pH.
abstract: Inward rectifier K+ channels of the Kir1.1 (ROMK) and Kir4.1 subtype are predominantly expressed in epithelial cells where they are responsible for K+ transport across the plasma membrane. Uniquely among the members of the Kir family, these channels are gated by intracellular pH in the physiological range. pH-gating involves structural rearrangements in cytoplasmic domains and the P-loop of the Kir protein. The energy for the gating transition is delivered by protonation of a lysine residue that is located prior to the first transmembrane segment and serves as a 'pH sensor'. The anomalous titration required for lysine operating in the neutral pH range results from its close interaction with two positively charged arginines from the distant N- and C-termini termed the R/K/R triad. Disturbance of this triad as results from a number of point mutations found in patients with hyperprostaglandin E syndrome (HPS) increases the pKa of the pH sensor and results in channels being permanently inactivated under physiological conditions. This article will focus on the mechanism of pH-gating, its implications for the tertiary structure of Kir proteins and on its significance for the pathogenesis of HPS.
authors.affiliation: Department of Physiology II, University of Tübingen, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Schulte
authors.forename: B
authors.initials: B
authors.lastname: Fakler
mesh_terms: D000818:Animals; D002412:Cations / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D003001:Cloning, Molecular; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007231:Infant, Newborn; D007424:Intracellular Fluid / Q000737:chemistry; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D017136:Ion Transport / Q000187:drug effects; D007668:Kidney / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D017354:Point Mutation; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D013577:Syndrome; D014981:Xenopus
chemical_list: D002412:Cations; D002712:Chlorides; D015221:Potassium Channels; D011993:Recombinant Fusion Proteins; D013439:Sulfhydryl Reagents; D011188:Potassium