pH-dependent modulation of Kv1.3 inactivation: Role of His399

Sándor Samodi, Zoltán Varga, Péter Hajdu, John G. Starkus, Daniel I. Levy, Rezso Gáspár, György Panyi

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Abstract

The Kv1.3 K+ channel lacks N-type inactivation, but during prolonged depolarized periods it inactivates via the slow (P/C type) mechanism. It bears a titratable histidine residue in position 399 (equivalent of Shaker 449), a site known to influence the rate of slow inactivation. As opposed to several other voltage-gated K+ channels, slow inactivation of Kv1.3 is slowed when extracellular pH (pHO) is lowered under physiological conditions. Our findings are as follows. First, when His399 was mutated to a lysine, arginine, leucine, valine or tyrosine, extracellular acidification (pH 5.5) accelerated inactivation reminiscent of other Kv channels. Second, inactivation of the wild-type channel was accelerated by low pHO when the ionic strength of the external solution was raised. Inactivation of the H399K mutant was also accelerated by high ionic strength at pH 7.35 but not the inactivation of H399L. Third, after the external application of blocking barium ions, recovery of the wild-type current during washout was slower in low pH O. Fourth, the dissociation rate of Ba2+ was pH insensitive for both H399K and H399L. Furthermore, Ba2+ dissociation rates were equal for H399K and the wild type at pH 5.5 and were equal for H399L and the wild type at pH 7.35. These observations support a model in which the electric field of the protonated histidines creates a potential barrier for potassium ions just outside the external mouth of the pore that hinders their exit from the binding site controlling inactivation. In Kv1.3, this effect overrides the generally observed speeding of slow inactivation when pH O is reduced.

Original languageEnglish
Pages (from-to)C1067-C1076
JournalAmerican Journal of Physiology - Cell Physiology
Volume287
Issue number4 56-4
DOIs
Publication statusPublished - Oct 1 2004

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Keywords

  • Barium
  • Extracellular pH
  • High ionic strength
  • Histidine
  • Potassium channel

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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