DYN-Mediated Internalization of KCNQ1/KCNE1 Channels under Sustained CPKC Activation

摘要: Chronic stimulation of PKC signaling pathways is a hallmark cardiac disease. Although QT prolongation and arrhythmias have been associated with disease, the mechanism underlying this has not fully understood. Using combination time-lapse confocal microscopy patch-clamp techniques we investigated time-dependent changes in subcellular localization channel activity KCNQ1/KCNE1 response to prolonged calcium dependent protein kinase C (cPKC) activation. Plasma membrane was reduced after 30-min cPKC activation, accompanied by decrease conductance. In addition, showed co-localization early-endosome marker Rab5. Dephospho-memetric mutation putative phosphorylation site KCEN1 (S102) abolished internalization current inhibition. Internalization also inhibited cPKC-specific inhibitors or co-expression dominant negative dynamin (DYN-K44A). Finally, inhibition Rab5 prenylation statins prevented cPKC-mediated internalization. Manipulations that inhibit did affect function absence stimulation. summary, our results show Dyn GTPases are key regulators for cell surface expression channels early endosomes under chronic Our findings indicate statin treatment may prevent electrophysiological remodeling pathophysiological condition upregulating levels at plasma cardiomyocytes.