Key result
In the Kv1.3 channel, extracellular acidification slows inactivation via protonation of His399, which creates a potential barrier hindering potassium ion exit from the binding site.
The His399 residue in the Kv1.3 channel is responsible for its unique slowing of slow inactivation under acidic conditions by creating a potential barrier for potassium ions.
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 Ba(2+) was pH insensitive for both H399K and H399L. Furthermore, Ba(2+) 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.
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Somodi et al. (2004) studied Kv1.3 K(+) channel slow inactivation. Extracellular acidification and His399 mutation vs. Wild-type channel at physiological pH was evaluated on Rate of slow inactivation and barium dissociation. In the Kv1.3 channel, extracellular acidification slows inactivation via protonation of His399, which creates a potential barrier hindering potassium ion exit from the binding site.
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