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XB-ART-39244
J Mol Cell Cardiol. May 1, 2009; 46 (5): 704-12.

PKC activation and PIP(2) depletion underlie biphasic regulation of IKs by Gq-coupled receptors.

Matavel A , Lopes CM .


Abstract
KCNQ1 is co-assembled with KCNE1 subunits in the heart to form the cardiac delayed rectifier K(+) current (IKs), which is one of the main currents responsible for myocyte repolarization. The most commonly inherited form of cardiac arrhythmias, long-QT syndrome type 1 (LQT1), is due to mutations on KCNQ1. Gq-coupled receptors (GqPCRs) are known to mediate positive inotropism in human ventricular myocardium. The mechanism of IKs current modulation by GqPCRs remains incompletely understood. Here we studied the molecular mechanisms underlying Gq regulation of the IKs channel. Heterologously expressed IKs (human KCNQ1/KCNE1 subunits) was measured in Xenopus oocytes, expressed together with GqPCRs. Our data from several GqPCRs shows that IKs is regulated in a biphasic manner, showing both an activation and an inhibition phase. Receptor-mediated inhibition phase was irreversible when recycling of agonist-sensitive pools of phosphatidylinositol-4,5-bisphosphate (PIP2) was blocked by the lipid kinase inhibitor wortmannin. In addition, stimulation of PIP(2) production, by overexpression of phosphatidylinositol-4-phosphate-5-kinase (PIP5-kinase), decreased receptor-mediated inhibition. The receptor-mediated activation phase was inhibited by the PKC inhibitor calphostin C and by a mutation in a putative PKC phosphorylation site in the KCNE1 subunit. Our results indicate that the depletion of membrane PIP(2) underlies receptor-mediated inhibition of IKs and that phosphorylation by PKC of the KCNE1 subunit underlies the GqPCR-mediated channel activation.

PubMed ID: 19233191
PMC ID: PMC2668609
Article link: J Mol Cell Cardiol.
Grant support: R01 HL033843-20A1 NHLBI NIH HHS , R01 HL033843-20A1 NHLBI NIH HHS , R01 HL033843-20A1 NHLBI NIH HHS , R01 HL033843-20A1 NHLBI NIH HHS , R01 HL033843-20A1 NHLBI NIH HHS , R01 HL033843-20A1 NHLBI NIH HHS

Genes referenced: arfgap1 kcne1 kcnq1
Antibodies referenced:
Morpholinos referenced:

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