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)P(2))
| Autor: | Aldo A. Rodríguez-Menchaca, Avia Rosenhouse-Dantsker, Scott K. Adney, Catherine V. Osborn, Irena Levitan, Qiong Yao Tang, Vasileios I. Petrou, Diomedes E. Logothetis, Huazhi Han, Gregory B. Kowalsky, Sergei Y. Noskov |
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| Rok vydání: | 2012 |
| Předmět: |
Phosphatidylinositol 4
5-Diphosphate Xenopus Amino Acid Motifs Molecular Sequence Data chemical and pharmacologic phenomena Gating Biology Biochemistry chemistry.chemical_compound immune system diseases Membrane Biology otorhinolaryngologic diseases Animals Humans Phosphatidylinositol Amino Acid Sequence Potassium Channels Inwardly Rectifying Molecular Biology Membrane potential Molecular switch Inward-rectifier potassium ion channel hemic and immune systems Cell Biology Cell biology Cytosol Cholesterol HEK293 Cells Phosphatidylinositol 4 5-bisphosphate chemistry embryonic structures Mutation Oocytes Function (biology) |
| Zdroj: | The Journal of biological chemistry. 287(48) |
| ISSN: | 1083-351X |
| Popis: | Cholesterol modulates inwardly rectifying potassium (Kir) channels.A two-way molecular cytosolic switch controls channel modulation by cholesterol and PI(4,5)P(2).Cholesterol and PI(4,5)P(2) induce a common gating pathway of Kir2.1 despite their opposite impact on channel function.These findings provide insights into structure-function relationship of ion channels and contribute to understanding of the mechanisms underlying their regulation by lipids. 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. |
| Databáze: | OpenAIRE |
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