Tw. Claydon et al., Inhibition of the K+ channel Kv1.4 by acidosis: protonation of an extracellular histidine slows the recovery from N-type inactivation, J PHYSL LON, 526(2), 2000, pp. 253-264
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.