KCNE1 Subunit Phosphorylation Leads to IKs Internalization in Response to Chronic Calcium-Dependent PKC Activation

Abstract

Decrease of the cardiac slowly activating delayed rectified K+ current (IKs), formed by KCNQ1 and KCNE1 subunits, is observed in a number of diseases states such as heart failure and diabetes and is associated with increased risk for cardiac arrhythmias and sudden death. Ca2+-dependent PKC isoforms (cPKC) are chronically activated in many pathological conditions. Recently, we found that sustained cPKC stimulation leads to KCNQ1 subunit internalization and decrease of IKs channel activity. Here, we show that KCNE1 is internalized together with KCNQ1 in response to sustained cPKC stimulus using immunostaining and confocal imaging. In addition, we show that KCNE1 is necessary for channel internalization independently of subunit stoichiometry both in heterologous expression systems and cardiomyocytes. Mutation of a PKC phosphorylation site shown to be important to cPKC acute regulation of the channel (KCNE1-S102A) was necessary to channel internalization. Altogether, our results suggest that KCNE1(S102) phosphorylation by cPKC leads to KCNQ1/KCNE1 internalization in response to sustained cPKC stimulus. Our results suggest that KCNE1(S102) is an important target for anti-arrhythmic drugs that would prevent IKs pathological remodeling leading to cardiac arrhythmias.