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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

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

Sándor Somodi,^1,* Zoltán Varga,^1,* Péter Hajdu,² John G. Starkus,³ Daniel I. Levy,⁴ Rezs Gáspár,¹ and György Panyi¹

¹Department of Biophysics and Cell Biology, Research Center for Molecular Medicine, and ²Cell Biophysics Research Group of the Hungarian Academy of Sciences, Department of Biophysics and Cell Biology, Medical and Health Science Center, University of Debrecen, H-4012 Debrecen, Hungary; ³Pacific Biomedical Research Center, Bekesy Laboratory of Neurobiology, University of Hawaii, Honolulu, Hawaii 96822; and ⁴Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520

Submitted 10 October 2003 ; accepted in final form 10 June 2004

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 (pH_o) 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 pH_o 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.

extracellular pH; potassium channel; histidine; barium; high ionic strength

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