Abstract

Kv1.5 is the principal molecular component of I_Kur, an atrial-specific K⁺ current in human myocytes that is suppressed by activation of protein kinase C (PKC). We examined the effect of phorbol 12-myristate 13-acetate (PMA), a direct activator of PKC, on Kv1.5 current. Although PMA had minimal effect when Kv1.5 was expressed alone, K⁺ currents derived from coexpression of Kvβ1.2 (but not another closely related β subunit, Kvβ1.3) with Kv1.5 were markedly reduced by PMA, associated with a small depolarizing shift in the voltage dependence of channel activation. Additional experiments with an inactive stereoisomer, 4α-PMA, and the PKC inhibitor chelerythrine indicated that the effects of PMA were mediated by PKC activation. Assembly of Kv1.5 in vivo with both β subunits was demonstrated, and all three K⁺ channel proteins were substrates for phosphorylation by PKC. These results demonstrate that coexpression of Kvβ1.2 enhances the response of Kv1.5 to PKC activation and that direct phosphorylation of K⁺ channel subunits is a potential molecular basis for the effect. Furthermore, they suggest that Kvβ1.2 may be a component of the I_Kur complex in human atrium.