부산대학교 도서관

G-protein-gated inwardly rectifying potassium (GIRK) channel activity is regulated by the membrane phospholipid, phosphatidylinositol-4,5-bisphosphate (PI 4,5P2). Constitutive activity of cardiac GIRK channels in atrial myocytes, that is implicated in atrial fibrillation (AF), is mediated via a protein kinase C-e (PKCe)-dependent mechanism. The novel PKC isoform, PKCe, is reported to enhance the activity of cardiac GIRK channels. Here, we report that PKCe stimulation leads to activation of GIRK channels in mouse atria and in human stem cell-derived atrial cardiomyocytes (iPSCs). We identified residue GIRK4(S418) which when mutated to Ala abolished, or to Glu, mimicked the effects of PKCe on GIRK currents. PKCe strengthened the interactions of the cardiac GIRK isoforms, GIRK4 and GIRK1/4 with PIP2, an effect that was reversed in the GIRK4(S418A) mutant. This mechanistic insight into the PKCe-mediated increase in channel activity because of GIRK4(S418) phosphorylation, provides a precise druggable target to reverse AF-related pathologies due to GIRK overactivity. [ABSTRACT FROM AUTHOR]