title: Silencing of Kir2 channels by caveolin-1: cross-talk with cholesterol.
abstract: 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 inwardly rectifying potassium channels Kir2.1 that play major roles in the regulation of membrane potentials 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 isolated from Cav-1(-/-) and wild-type 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 bone marrow-derived macrophages isolated from Cav-1(-/-) knockout mice. Thus, these studies indicate that Cav-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.
authors.affiliation: Section of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA hhan4@uic.edu levitan@uic.edu.
authors.forename: Huazhi
authors.initials: H
authors.lastname: Han
authors.affiliation: Section of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Avia
authors.initials: A
authors.lastname: Rosenhouse-Dantsker
authors.affiliation: Department of Physiology and Biophysics, University at Buffalo, SUNY, Buffalo, NY, 14214, USA.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Gnanasambandam
authors.affiliation: Section of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Epshtein
authors.affiliation: Departments of Anesthesiology and Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Physiology and Biophysics, University at Buffalo, SUNY, Buffalo, NY, 14214, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Sachs
authors.affiliation: Departments of Anesthesiology and Pharmacology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.affiliation: Section of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA hhan4@uic.edu levitan@uic.edu.
authors.forename: Irena
authors.initials: I
authors.lastname: Levitan
mesh_terms: D000200:Action Potentials; D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000502:physiology; D051379:Mice; D017354:Point Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying; D002784:Cholesterol