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

• DOI: 10.1016/j.bpj.2015.11.621
• Publication Date: 2016-02-16T14:30:15Z
• Authors: Xiaorong Xu Parks; Elsa Ronzier; Jin O-Uchi; Coeli M. Lopes
• Keywords: 0301 basic medicine; 03 medical and health sciences; Biophysics

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