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)

• Published in: The Journal of biological chemistry Vol. 287; no. 48; pp. 40266 - 40278
• Main Authors: Rosenhouse-Dantsker, Avia, Noskov, Sergei, Han, Huazhi, Adney, Scott K., Tang, Qiong-Yao, Rodríguez-Menchaca, Aldo A., Kowalsky, Gregory B., Petrou, Vasileios I., Osborn, Catherine V., Logothetis, Diomedes E., Levitan, Irena
• Format: Journal Article
• Language: English
• Published: 9650 Rockville Pike, Bethesda, MD 20814, U.S.A Elsevier Inc 23-11-2012; American Society for Biochemistry and Molecular Biology
• Subjects: Cholesterol; Ion Channels; Kir Channels; Lipids; Membrane Biology; Membrane Lipids; Potassium Channels; Potassium Channels; Lipids; Membrane Lipids; Ion Channels; Kir Channels; Cholesterol
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.336339

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.
Background: Cholesterol modulates inwardly rectifying potassium (Kir) channels.
Results: A two-way molecular cytosolic switch controls channel modulation by cholesterol and PI(4,5)P2.
Conclusion: Cholesterol and PI(4,5)P2 induce a common gating pathway of Kir2.1 despite their opposite impact on channel function.
Significance: These findings provide insights into structure-function relationship of ion channels and contribute to understanding of the mechanisms underlying their regulation by lipids.