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Biophysical Journal 87:2407-2418 (2004)
© 2004 The Biophysical Society

K+ Activation of Kir3.1/Kir3.4 and Kv1.4 K+ Channels Is Regulated by Extracellular Charges

T. W. Claydon, S. Y. Makary, K. M. Dibb and M. R. Boyett

School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom

Correspondence: Address reprint requests to M. R. Boyett, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK. Tel.: 44-113-3434298; Fax: 44-113-3434224; E-mail: m.r.boyett{at}leeds.ac.uk.

K+ activates many inward rectifier and voltage-gated K+ channels. In each case, an increase in K+ current through the channel can occur despite a reduced driving force. We have investigated the molecular mechanism of K+ activation of the inward rectifier K+ channel, Kir3.1/Kir3.4, and the voltage-gated K+ channel, Kv1.4. In the Kir3.1/Kir3.4 channel, mutation of an extracellular arginine residue, R155, in the Kir3.4 subunit markedly reduced K+ activation of the channel. The same mutation also abolished Mg2+ block of the channel. Mutation of the equivalent residue in Kv1.4 (K532) abolished K+ activation as well as C-type inactivation of the Kv1.4 channel. Thus, whereas C-type inactivation is a collapse of the selectivity filter, K+ activation could be an opening of the selectivity filter. K+ activation of the Kv1.4 channel was enhanced by acidic pH. Mutation of an extracellular histidine residue, H508, that mediates the inhibitory effect of protons on Kv1.4 current, abolished both K+ activation and the enhancement of K+ activation at acidic pH. These results suggest that the extracellular positive charges in both the Kir3.1/Kir3.4 and the Kv1.4 channels act as "guards" and regulate access of K+ to the selectivity filter and, thus, the open probability of the selectivity filter. Furthermore, these data suggest that, at acidic pH, protonation of H508 inhibits current through the Kv1.4 channel by decreasing K+ access to the selectivity filter, thus favoring the collapse of the selectivity filter.




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