Modulation of the human Kv1.5 channel by protein kinase C activation: role of the Kvbeta1.2 subunit.
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 Kvbeta1.2 (but not another closely related beta subunit, Kvbeta1.3) 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, 4alpha-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 beta subunits was demonstrated, and all three K(+) channel proteins were substrates for phosphorylation by PKC. These results demonstrate that coexpression of Kvbeta1.2 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 Kvbeta1.2 may be a component of the I(Kur) complex in human atrium.
Department of Medicine, Preston Research Building Rm 559, Vanderbilt University School of Medicine, 23rd Avenue South at Pierce Avenue, Nashville, TN 37232-6602, USA.
Christine P
CP
Williams
NingNing
N
Hu
Wangzhen
W
Shen
Amy B
AB
Mashburn
Katherine T
KT
Murray
D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D051663:Kv1.2 Potassium Channel; D051666:Kv1.5 Potassium Channel; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011493:Protein Kinase C / Q000378:metabolism*; D021122:Protein Subunits; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C496969:KCNA2 protein, human; C496981:KCNA5 protein, human; D051663:Kv1.2 Potassium Channel; D051666:Kv1.5 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate