ArticleThe Journal of biological chemistry2012
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)).
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Membrane Cholesterol Interactions with Proteins in Hypercholesterolemia-Induced Endothelial Dysfunction.Current atherosclerosis reports · 2023Review
- From Crosstalk to Synergism: The Combined Effect of Cholesterol and PI(4,5)PAdvances in experimental medicine and biology · 2023Review
- PI(4,5)PAdvances in experimental medicine and biology · 2023Article
- Phosphatidylinositol 4,5-Bisphosphate and Cholesterol Regulators of the Calcium-Activated Chloride Channels TMEM16A and TMEM16B.Advances in experimental medicine and biology · 2023Article
- Cholesterol and PIPAdvances in experimental medicine and biology · 2023Article
- A molecular switch controls the impact of cholesterol on a Kir channel.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- A Cholesterol Dimer Stabilizes the Inactivated State of an Inward-Rectifier Potassium Channel.Angewandte Chemie (International ed. in English) · 2022Article
- Targeting Lipid-Ion Channel Interactions in Cardiovascular Disease.Frontiers in cardiovascular medicine · 2022Article
- Defining how multiple lipid species interact with inward rectifier potassium (Kir2) channels.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Hypercholesterolemia-Induced Loss of Flow-Induced Vasodilation and Lesion Formation in Apolipoprotein E-Deficient Mice Critically Depend on Inwardly Rectifying KJournal of the American Heart Association · 2018Article
- Styrax blocks inward and outward current of Kir2.1 channel.Channels (Austin, Tex.) · 2017Article
- Lovastatin-Induced Phosphatidylinositol-4-Phosphate 5-Kinase Diffusion from Microvilli Stimulates ROMK Channels.Journal of the American Society of Nephrology : JASN · 2015Article
- Identification of a cholesterol-binding pocket in inward rectifier K(+) (Kir) channels.Biophysical journal · 2014Article
- Interplay Between Lipid Modulators of Kir2 Channels: Cholesterol and PIP2.Computational and structural biotechnology journal · 2014Article
- Cholesterol binding to ion channels.Frontiers in physiology · 2014Review
- Identification of novel cholesterol-binding regions in Kir2 channels.The Journal of biological chemistry · 2013Article
- Cholesterol sensitivity of KIR2.1 depends on functional inter-links between the N and C termini.Channels (Austin, Tex.)Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundCholesterol modulates inwardly rectifying potassium (Kir) channels.
resultsA two-way molecular cytosolic switch controls channel modulation by cholesterol and PI(4,5)P(2).
conclusionCholesterol and PI(4,5)P(2) 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. 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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