PubMed 25038242

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Title: Silencing of Kir2 channels by caveolin-1: cross-talk with cholesterol.

Authors: Huazhi Han, Avia Rosenhouse-Dantsker, Radhakrishnan Gnanasambandam, Yulia Epshtein, Zhenlong Chen, Frederick Sachs, Richard D Minshall, Irena Levitan

Journal, date & volume: J. Physiol. (Lond.), 2014 Jul 18 , ,

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A growing number of studies show that different types of ion channels localize in caveolae and are regulated by the level of membrane cholesterol. Furthermore, it has been proposed that cholesterol-induced regulation of ion channels might be attributed to partitioning into caveolae and association with caveolin-1 (Cav-1). We tested, therefore, whether Cav-1 regulates the function of Kir2.1 channels that play major roles in the regulation of membrane potential of numerous mammalian cells. Our earlier studies demonstrated that Kir2.1 channels are cholesterol sensitive. In this study, we show that Kir2.1 channels co-immunoprecipitate with Cav-1 and that co-expression of Kir2.1 channels with Cav-1 in HEK293 cells results in suppression of Kir2 current indicating that Cav-1 is a negative regulator of Kir2 function. These observations are confirmed by comparing Kir currents in Bone-Marrow Derived Macrophages (BMDMs) isolated from Cav1(-/-) and WT animals. We also show, however, that Kir2 channels maintain their sensitivity to cholesterol in HEK293 cells that have very low levels of endogenous Cav-1 and in BMDMs isolated from Cav1(-/-) knockout mice.  Thus, these studies indicate that caveolin-1 and/or intact caveolae are not required for cholesterol sensitivity of Kir channels. Moreover, a single point mutation of Kir2.1, L222I that abrogates the sensitivity of the channels to cholesterol also abolishes their sensitivity to Cav-1 suggesting that the two modulators regulate Kir2 channels via a common mechanism. This article is protected by copyright. All rights reserved.