Abstract
The slow cardiac delayed rectifier current (IKs) is formed by KCNQ1 and KCNE1 subunits and is one of the major repolarizing currents in the heart. Decrease of IKs currents either due to inherited mutations or pathological remodeling is associated with increased risk for cardiac arrhythmias and sudden death. Ca2+-dependent PKC isoforms (cPKC) are chronically activated in heart disease and diabetes. Recently, we found that sustained stimulation of the calcium-dependent PKCβII isoform leads to decrease in KCNQ1 subunit membrane localization and KCNQ1/KCNE1 channel activity, although the role of KCNE1 in this regulation was not explored. Here, we show that the auxiliary KCNE1 subunit expression is necessary for channel internalization. A mutation in a KCNE1 phosphorylation site (KCNE1(S102A)) abolished channel internalization in both heterologous expression systems and cardiomyocytes. Altogether, our results suggest that KCNE1(S102) phosphorylation by PKCβII leads to KCNQ1/KCNE1 channel internalization in response to sustained PKC stimulus, while leaving KCNQ1 homomeric channels in the membrane. This preferential internalization is expected to have strong impact on cardiac repolarization. Our results suggest that KCNE1(S102) is an important anti-arrhythmic drug target to prevent IKs pathological remodeling leading to cardiac arrhythmias.
Highlights
Voltage-gated potassium channels are ubiquitous and are major regulators of electrical properties of excitable cells
We have recently reported that chronic stimulation of Ca2+-dependent PKC isoforms (cPKC) reduced the membrane localization of KCNQ1/KCNE1 channels and decreased channel function [20]
In order to study the role of KCNE1 subunit on cPKC-induced internalization of channels, we investigated the effect of chronic stimulation of cPKC on channel membrane localization in cells expressing KCNQ1-GFP either alone or together with the auxiliary subunit KCNE1
Summary
Voltage-gated potassium channels are ubiquitous and are major regulators of electrical properties of excitable cells. These potassium channels are assembled by four alpha subunits, each containing six transmembrane regions. Members of the single transmembrane KCNE family frequently co-assemble with potassium channel alpha subunits to form the native channel. For the cardiac potassium channel IKs, the alpha subunit (KCNQ1) and the beta subunit (KCNE1) are necessary to form the native channel [1, 2]. Expression of the KCNE1 subunit was shown to affect channel regulation by protein kinase A [6] and increase channel sensitivity to PIP2 100-fold over the KCNQ1 subunit expressed alone [7]
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