ArticleProceedings of the National Academy of Sciences of the United States of America2009
Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 108 citations in OpenAlex.
- Potassium channels in vascular smooth muscle cells.Physiological reviews · 2026Review
- Ionic regulation of cancer cell stiffness and metastatic colonization via the MRTFA-KCNMB1 axis.Developmental cell · 2026Article
- Choline attenuates bilirubin induced effects on tyrosine phosphorylation and distribution in lipid rafts of L1 cell adhesion molecule in vivo.Pediatric research · 2026Article
- Ionic Regulation of Mechanosurveillance and Metastasis via the MRTFA/KCNMB1 Axis.bioRxiv : the preprint server for biology · 2026Article
- Mutagenesis-Centered Integrative Approaches for Identifying Binding Sites in Ion Channels and Uncovering Modulatory Mechanisms.Advances in experimental medicine and biology · 2026Review
- Targeting the hERG1/β1 integrin complex in lipid rafts potentiates statins anti-cancer activity in pancreatic cancer.Cell death discovery · 2025Article
- Inverse relationship between LDL-C/HDL-C ratio and atrial fibrillation in chronic kidney disease patients.Scientific reports · 2024Article
- Choline supplementation mitigates effects of bilirubin in cerebellar granule neurons in vitro.Pediatric research · 2024Article
- Cholesterol regulation of mechanosensitive ion channels.Frontiers in cell and developmental biology · 2024Review
- From Crosstalk to Synergism: The Combined Effect of Cholesterol and PI(4,5)PAdvances in experimental medicine and biology · 2023Review
- Association between cardiovascular risk factors and atrial fibrillation.Frontiers in cardiovascular medicine · 2023Review
- Cholesterol-induced suppression of Kir2 channels is mediated by decoupling at the inter-subunit interfaces.iScience · 2022Article
- A Cholesterol Dimer Stabilizes the Inactivated State of an Inward-Rectifier Potassium Channel.Angewandte Chemie (International ed. in English) · 2022Article
- Cholesterol-Induced Suppression of Endothelial Kir Channels Is a Driver of Impairment of Arteriolar Flow-Induced Vasodilation in Humans.Hypertension (Dallas, Tex. : 1979) · 2022Article
- The Relationship between Blood Lipids and Risk of Atrial Fibrillation: Univariable and Multivariable Mendelian Randomization Analysis.Nutrients · 2021Article
- Structural insights into GIRK2 channel modulation by cholesterol and PIPCell reports · 2021Article
- From Bench to Biomolecular Simulation: Phospholipid Modulation of Potassium Channels.Journal of molecular biology · 2021Review
- Bilirubin inhibits lipid raft dependent functions of L1 cell adhesion molecule in rat pup cerebellar granule neurons.Pediatric research · 2021Article
- Kir Channel Molecular Physiology, Pharmacology, and Therapeutic Implications.Handbook of experimental pharmacology · 2021Review
- Methyl-Beta-Cyclodextrin Restores KJournal of Alzheimer's disease reports · 2021Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
A variety of ion channels are regulated by cholesterol, a major lipid component of the plasma membrane whose excess is associated with multiple pathological conditions. However, the mechanism underlying cholesterol sensitivity of ion channels is unknown. We have recently shown that an increase in membrane cholesterol suppresses inwardly rectifying K(+) (Kir2) channels that are responsible for maintaining membrane potential in a variety of cell types. Here we show that cholesterol sensitivity of Kir2 channels depends on a specific region of the C terminus of the cytosolic domain of the channel, the CD loop. Within this loop, the L222I mutation in Kir2.1 abrogates the sensitivity of the channel to cholesterol whereas a reverse mutation in the corresponding position in Kir2.3, I214L, has the opposite effect, increasing cholesterol sensitivity. Furthermore, the L222I mutation has a dominant negative effect on cholesterol sensitivity of Kir2.1 WT. Mutations of 2 additional residues in the CD loop in Kir2.1, N216D and K219Q, partially affect the sensitivity of the channel to cholesterol. Yet, whereas these mutations have been shown to affect activation of the channel by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)], other mutations outside the CD loop that have been previously shown to affect activation of the channel by PI(4,5)P(2) had no effect on cholesterol sensitivity. Mutations of the lipid-facing residues of the outer transmembrane helix also had no effect. These findings provide insights into the structural determinants of the sensitivity of Kir2 channels to cholesterol, and introduce the critical role of the cytosolic domain in cholesterol dependent channel regulation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.