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

1. Acidosis alters the transient outward current, i(to), in the heart. We h ave studied the mechanism underlying the effect of acidosis on one of the K + channels, Kv1.4 (heterologously expressed in Xenopus laevis oocytes), kno wn to underlie i(to). 2. At pH 6.5, wild-type Kv1.4 current was inhibited during repetitive pulsi ng, 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 (ei ther the first or second) of the N-terminal inactivation ball domains. Howe ver, deletion of both the N-terminal inactivation ball domains greatly redu ced 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 acidosi s sensitivity 5. Replacement of an extracellular histidine with a glutamine residue (H508 Q) abolished the slowing of recovery by acidosis. Reduction of C-type inact ivation by raising the bathing K+ concentration or by the mutation K532Y al so abolished the slowing. 6. It is concluded that binding of protons to H508 enhances C-type inactiva tion and this causes a slowing of recovery from N-type inactivation and, th us, an inhibition of current during repetitive pulsing.