Distant Cytosolic Residues Mediate a Two-way Molecular Switch That Controls the Modulation of Inwardly Rectifying Potassium (Kir) Channels by Cholesterol and Phosphatidylinositol 4,5-Bisphosphate (PI(4,5)P2) |
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Authors: | Avia Rosenhouse-Dantsker Sergei Noskov Huazhi Han Scott K Adney Qiong-Yao Tang Aldo A Rodríguez-Menchaca Gregory B Kowalsky Vasileios I Petrou Catherine V Osborn Diomedes E Logothetis Irena Levitan |
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Institution: | From the ‡Department of Medicine, Pulmonary Section, University of Illinois, Chicago, Illinois 60612.;§Institute for Biocomplexity and Informatics and Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada, and ;¶Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 |
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Abstract: | Inwardly rectifying potassium (Kir) channels play an important role in setting the resting membrane potential and modulating membrane excitability. An emerging feature of several Kir channels is that they are regulated by cholesterol. However, the mechanism by which cholesterol affects channel function is unclear. Here we show that mutations of two distant Kir2.1 cytosolic residues, Leu-222 and Asn-251, form a two-way molecular switch that controls channel modulation by cholesterol and affects critical hydrogen bonding. Notably, these two residues are linked by a residue chain that continues from Asn-251 to connect adjacent subunits. Furthermore, our data indicate that the same switch also regulates the sensitivity of the channels to phosphatidylinositol 4,5-bisphosphate, a phosphoinositide that is required for activation of Kir channels. Thus, although cholesterol and phosphatidylinositol 4,5-bisphosphate do not interact with the same region of Kir2.1, these different modulators induce a common gating pathway of the channel. |
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Keywords: | Cholesterol Ion Channels Lipids Membrane Lipids Potassium Channels Kir Channels |
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