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Inhibition of the K⁺ channel Kv1.4 by acidosis: protonation of an extracellular histidine slows the recovery from N-type inactivation

T. W. Claydon, M. R. Boyett, A. Sivaprasadarao, K. Ishii *, J. M. Owen, H. A. O'Beirne, R. Leach †, K. Komukai and C. H. Orchard

1. Acidosis alters the transient outward current, i_to, in the heart. We have studied the mechanism underlying the effect of acidosis on one of the K⁺ channels, Kv1.4 (heterologously expressed in Xenopus laevis oocytes), known to underlie i_to.

2. At pH 6·5, wild-type Kv1.4 current was inhibited during repetitive pulsing, in part as a result of a slowing of recovery from N-type inactivation.

3. Acidosis still caused slowing of recovery after deletion of just one (either the first or second) of the N-terminal inactivation ball domains. However, deletion of both the N-terminal inactivation ball domains greatly reduced the inhibition.

4. As well as the N-terminus, other parts of the channel are also required for the effect of acidosis, because, whereas the transfer of the N-terminus of Kv1.4 to Kv1.2 conferred N-type inactivation, it did not confer acidosis sensitivity.

5. Replacement of an extracellular histidine with a glutamine residue (H508Q) abolished the slowing of recovery by acidosis. Reduction of C-type inactivation by raising the bathing K⁺ concentration or by the mutation K532Y also abolished the slowing.

6. It is concluded that binding of protons to H508 enhances C-type inactivation and this causes a slowing of recovery from N-type inactivation and, thus, an inhibition of current during repetitive pulsing.

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