Abstract
Kv1.5 is the principal molecular component of IKur, 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 IKur complex in human atrium.
Footnotes
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This work was supported by grants from the National Institutes of Health (R01 HL47599) and the American Heart Association (Southeast Affiliate).
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DOI: 10.1124/jpet.102.033357
- Abbreviations:
- AF
- atrial fibrillation
- PKC
- protein kinase C
- PMA
- phorbol 12-myristate 13-acetate
- PKA
- cAMP-dependent protein kinase (protein kinase A)
- HA
- hemagglutinin
- Received January 18, 2002.
- Accepted April 25, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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