5 years ago

Distinct protein kinase C isoenzyme mediates inhibitory effects of different G-protein coupled receptors on cardiac rapidly activating delayed rectifier K+ current

Yanfang Xu, Hua Zhang, Xueli Liu, Li Shen, Yuhong Wang
Background and purpose Elevated angiotensin II (Ang II) and sympathetic activity contributes to high risk of ventricular arrhythmias in heart diseases. The rapidly activating delayed rectifier K+ current (IKr) carried by the hERG protein plays a critical role in cardiac repolarization; and a reduction of IKr is involved in increased cardiac arrhythmogenicity. Studies have shown that stimulation of α1A-adrenoreceptors (α1AAR) or Ang II type 1 receptor (AT1R) inhibits IKr via protein kinase C (PKC). This study was designed to identify PKC isoenzymes responsible for mediating the inhibition of IKr by α1AAR and AT1R activation. Experimental approach The whole-cell patch-clamp technique was used to record IKr in guinea-pig cardiomyocytes and HEK293 cells co-transfected with hERG and α1AAR or AT1R genes. Key results A broad PKC inhibitor Gö6983 (not inhibiting PKCε) and a selective cPKC inhibitor Gö6976, as well as PKCα-specific inhibitor peptide blocked the inhibitory action of α1AAR agonist A61603 on IKr. In contrast, those inhibitors did not affect the reduction of IKr by AT1R activation, whereas the PKCε-selective inhibitor peptide significantly antagonized the effect. The effects of Ang II and PKCε activator peptide were blunted in mutant hERG in which 17 among 18 PKC phosphorylation sites were deleted, whereas a deletion of the N-terminus of the hERG channel selectively prevented the inhibition elicited by A61603 and the cPKC activator peptide. Conclusions and Implications Our results indicated that inhibitions of IKr by activation of α1AAR and AT1R were respectively mediated by PKCα and PKCε isoforms through different molecular mechanisms.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bph.14049

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