A Molecular Switch Controls the Impact of Cholesterol on a Kir Channel

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2022 Mar 25

PMID 35333652

Authors

Valentina Corradi

Anna N Bukiya

Williams E Miranda

Meng Cui

Leigh D Plant

Diomedes E Logothetis

D Peter Tieleman

Sergei Y Noskov

Avia Rosenhouse-Dantsker

Affiliations

Soon will be listed here.

Abstract

SignificanceCholesterol is one of the main components found in plasma membranes and is involved in lipid-dependent signaling enabled by integral membrane proteins such as inwardly rectifying potassium (Kir) channels. Similar to other ion channels, most of the Kir channels are down-regulated by cholesterol. One of the very few notable exceptions is Kir3.4, which is up-regulated by this important lipid. Here, we discovered and characterized a molecular switch that controls the impact (up-regulation vs. down-regulation) of cholesterol on Kir3.4. Our results provide a detailed molecular mechanism of tunable cholesterol regulation of a potassium channel.

Citing Articles

Cholesterol metabolism and intrabacterial potassium homeostasis are intrinsically related in .

Chen Y, Hagopian B, Tan S bioRxiv. 2024; .

PMID: 39605342 PMC: 11601456. DOI: 10.1101/2024.11.10.622811.

Molecular mechanism of GIRK2 channel gating modulated by cholesteryl hemisuccinate.

Cui M, Lu Y, Ma X, Logothetis D Front Physiol. 2024; 15:1486362.

PMID: 39493862 PMC: 11527606. DOI: 10.3389/fphys.2024.1486362.

Direct modulation of G protein-gated inwardly rectifying potassium (GIRK) channels.

Nguyen H, Glaaser I, Slesinger P Front Physiol. 2024; 15:1386645.

PMID: 38903913 PMC: 11187414. DOI: 10.3389/fphys.2024.1386645.

Mycobacterium tuberculosis response to cholesterol is integrated with environmental pH and potassium levels via a lipid metabolism regulator.

Chen Y, MacGilvary N, Tan S PLoS Genet. 2024; 20(1):e1011143.

PMID: 38266039 PMC: 10843139. DOI: 10.1371/journal.pgen.1011143.

Identification of Potential Modulators of a Pathogenic G Protein-Gated Inwardly Rectifying K Channel 4 Mutant: Investigation in the Context of Drug Discovery for Hypertension.

Pitsillou E, Logothetis A, Liang J, El-Osta A, Hung A, AbuMaziad A Molecules. 2023; 28(24).

PMID: 38138436 PMC: 10745636. DOI: 10.3390/molecules28247946.

References

Nishida M, Cadene M, Chait B, MacKinnon R . Crystal structure of a Kir3.1-prokaryotic Kir channel chimera. EMBO J. 2007; 26(17):4005-15. PMC: 1994128. DOI: 10.1038/sj.emboj.7601828. View

Romanenko V, Fang Y, Byfield F, Travis A, Vandenberg C, Rothblat G . Cholesterol sensitivity and lipid raft targeting of Kir2.1 channels. Biophys J. 2004; 87(6):3850-61. PMC: 1304896. DOI: 10.1529/biophysj.104.043273. View

Phillips J, Hardy D, Maia J, Stone J, Ribeiro J, Bernardi R . Scalable molecular dynamics on CPU and GPU architectures with NAMD. J Chem Phys. 2020; 153(4):044130. PMC: 7395834. DOI: 10.1063/5.0014475. View

LeMasurier M, Heginbotham L, Miller C . KcsA: it's a potassium channel. J Gen Physiol. 2001; 118(3):303-14. PMC: 2229506. DOI: 10.1085/jgp.118.3.303. View

Tao X, Avalos J, Chen J, MacKinnon R . Crystal structure of the eukaryotic strong inward-rectifier K+ channel Kir2.2 at 3.1 A resolution. Science. 2009; 326(5960):1668-74. PMC: 2819303. DOI: 10.1126/science.1180310. View

Dopico A, Bukiya A, Singh A . Large conductance, calcium- and voltage-gated potassium (BK) channels: regulation by cholesterol. Pharmacol Ther. 2012; 135(2):133-50. PMC: 3383457. DOI: 10.1016/j.pharmthera.2012.05.002. View

Bolotina V, Omelyanenko V, Heyes B, Ryan U, Bregestovski P . Variations of membrane cholesterol alter the kinetics of Ca2(+)-dependent K+ channels and membrane fluidity in vascular smooth muscle cells. Pflugers Arch. 1989; 415(3):262-8. DOI: 10.1007/BF00370875. View

Mehmood S, Corradi V, Choudhury H, Hussain R, Becker P, Axford D . Structural and Functional Basis for Lipid Synergy on the Activity of the Antibacterial Peptide ABC Transporter McjD. J Biol Chem. 2016; 291(41):21656-21668. PMC: 5076835. DOI: 10.1074/jbc.M116.732107. View

Wu C, Su M, Chi J, Chen W, Hsu H, Lee Y . The effect of hypercholesterolemia on the sodium inward currents in cardiac myocyte. J Mol Cell Cardiol. 1995; 27(6):1263-9. DOI: 10.1016/s0022-2828(05)82388-0. View

10.

Meuser D, Splitt H, Wagner R, Schrempf H . Exploring the open pore of the potassium channel from Streptomyces lividans. FEBS Lett. 2000; 462(3):447-52. DOI: 10.1016/s0014-5793(99)01579-3. View

11.

Crowley J, Treistman S, Dopico A . Cholesterol antagonizes ethanol potentiation of human brain BKCa channels reconstituted into phospholipid bilayers. Mol Pharmacol. 2003; 64(2):365-72. DOI: 10.1124/mol.64.2.365. View

12.

Monticelli L, Kandasamy S, Periole X, Larson R, Tieleman D, Marrink S . The MARTINI Coarse-Grained Force Field: Extension to Proteins. J Chem Theory Comput. 2015; 4(5):819-34. DOI: 10.1021/ct700324x. View

13.

Bukiya A, Vaithianathan T, Toro L, Dopico A . The second transmembrane domain of the large conductance, voltage- and calcium-gated potassium channel beta(1) subunit is a lithocholate sensor. FEBS Lett. 2008; 582(5):673-8. PMC: 2665905. DOI: 10.1016/j.febslet.2008.01.036. View

14.

Shlyonsky V, Mies F, Sariban-Sohraby S . Epithelial sodium channel activity in detergent-resistant membrane microdomains. Am J Physiol Renal Physiol. 2002; 284(1):F182-8. DOI: 10.1152/ajprenal.00216.2002. View

15.

Romanenko V, Rothblat G, Levitan I . Modulation of endothelial inward-rectifier K+ current by optical isomers of cholesterol. Biophys J. 2002; 83(6):3211-22. PMC: 1302398. DOI: 10.1016/S0006-3495(02)75323-X. View

16.

Rosenhouse-Dantsker A, Leal-Pinto E, Logothetis D, Levitan I . Comparative analysis of cholesterol sensitivity of Kir channels: role of the CD loop. Channels (Austin). 2009; 4(1):63-6. PMC: 2907253. DOI: 10.4161/chan.4.1.10366. View

17.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

18.

Bukiya A, Osborn C, Kuntamallappanavar G, Toth P, Baki L, Kowalsky G . Cholesterol increases the open probability of cardiac KACh currents. Biochim Biophys Acta. 2015; 1848(10 Pt A):2406-13. DOI: 10.1016/j.bbamem.2015.07.007. View

19.

Whorton M, MacKinnon R . Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium. Cell. 2011; 147(1):199-208. PMC: 3243363. DOI: 10.1016/j.cell.2011.07.046. View

20.

Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y . Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev. 2010; 90(1):291-366. DOI: 10.1152/physrev.00021.2009. View