Advertisement

Chiral Specificity of Cholesterol Orientation Within Cholesterol Binding Sites in Inwardly Rectifying K+ Channels

  • Nicolas Barbera
  • Irena LevitanEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1115)

Abstract

Cholesterol is an integral component of cellular membranes and has been shown to be an important functional regulator for many different ion channels, including inwardly rectifying potassium (Kir) channels. Consequently, understanding the molecular mechanisms underlying this regulation represents a critical field of study. Broadly speaking, cholesterol can mediate ion channel function either directly by binding to specific sites or indirectly by altering surrounding membrane properties. Owing to the similar effects of cholesterol and its chiral isomers (epicholesterol and ent-cholesterol) on membrane properties, comparative analysis of these sterols can be an effective tool for discriminating between these direct and indirect effects. Indeed, this strategy was used to demonstrate the direct effect of cholesterol on Kir channel function. However, while this approach can discriminate between direct and indirect effects, it does not account for the promiscuity of cholesterol binding sites, which can potentially accommodate cholesterol or its chiral isomers. In this chapter, we use docking analyses to explore the idea that the specificity of cholesterol’s effect on Kir channels is dependent on the specific orientation of cholesterol within its putative binding pocket which its chiral isomers cannot replicate, even when bound themselves.

Keywords

Kir channels Cholesterol binding Cholesterol stereoisomers 

Notes

Acknowledgements

We are very grateful to Ibra Fancher for the critical reading of the manuscript. We thank Manuela Ayee for critical discussions and Victor Romanenko for contributing GLC measurements shown in Fig. 2. We also thank Mr. Gregory Kowalsky for his help in designing Figs. 2 and 3. This work was supported by the National Institute of Health grants HL073965 and HL083298 (to I.L.).

References

  1. 1.
    Romanenko VG, Rothblat GH, Levitan I. Modulation of endothelial inward-rectifier K+ current by optical isomers of cholesterol. Biophys J. 2002;83(6):3211–22.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Addona GH, Sandermann H, Kloczewiak MA, Miller KW. Low chemical specificity of the nicotinic acetylcholine receptor sterol activation site. Biochim Biophys Acta Biomembr. 2003;1609(2):177–82.CrossRefGoogle Scholar
  3. 3.
    Romanenko VG, Rothblat GH, Levitan I. Sensitivity of volume-regulated anion current to cholesterol structural analogues. J Gen Physiol. 2004;123(1):77–88.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Bukiya AN, Singh AK, Parrill AL, Dopico AM. The steroid interaction site in transmembrane domain 2 of the large conductance, voltage-and calcium-gated potassium (BK) channel accessory β1 subunit. Proc Natl Acad Sci. 2011;108(50):20207–12.PubMedCrossRefGoogle Scholar
  5. 5.
    Picazo-Juarez G, Romero-Suarez S, Nieto-Posadas A, Llorente I, Jara-Oseguera A, Briggs M, et al. Identification of a binding motif in the S5 helix that confers cholesterol sensitivity to the TRPV1 ion channel. J Biol Chem. 2011;286(28):24966–76.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Demel RA, Bruckdorfer KR, van Deenen LLM. The effect of sterol structure on the permeability of liposomes to glucose, glycerol and Rb+. Biochim Biophys Acta. 1972;255:321–30.PubMedCrossRefGoogle Scholar
  7. 7.
    Westover EJ, Covey DF. The enantiomer of cholesterol. J Membr Biol. 2004;202(2):61.PubMedCrossRefGoogle Scholar
  8. 8.
    Gimpl G, Burger K, Fahrenholz F. Cholesterol as modulator of receptor function. Biochemistry. 1997;36:10959–74.PubMedCrossRefGoogle Scholar
  9. 9.
    Xu X, London E. The effect of sterol structure on membrane lipid domains reveals how cholesterol can induce lipid domain formation. Biochemistry. 2000;39:843–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y, et al. International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacol Rev. 2005;57(4):509–26.PubMedCrossRefGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    Levitan I, Ahn SJ, Fancher I, Rosenhouse-Dantsker A. Physiological roles and cholesterol sensitivity of endothelial inwardly-rectifying K+ channels: specific cholesterol-protein interactions through non annular binding sites. In: Levitan I, Dopico A, editors. Vascular ion channels in health and disease. Berlin: Springer; 2016.CrossRefGoogle Scholar
  13. 13.
    Levitan I. Cholesterol and Kir channels. IUBMB Life. 2009;61:781–90.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Zaritsky JJ, Eckman DM, Wellman GC, Nelson MT, Schwarz TL. Targeted disruption of Kir2. 1 and Kir2. 2 genes reveals the essential role of the inwardly rectifying K+ current in K+-mediated vasodilation. Circ Res. 2000;87(2):160–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Miake J, Marban E, Nuss HB. Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression. J Clin Invest. 2003;111:1529–36.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Piao L, Li J, McLerie M, Lopatin A. Transgenic upregulation of IK1 in the mouse heart is proarrhythmic. Basic Res Cardiol. 2007;102(5):416–28.PubMedCrossRefGoogle Scholar
  17. 17.
    Filosa JA, Bonev AD, Straub SV, Meredith AL, Wilkerson MK, Aldrich RW, et al. Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat Neurosci. 2006;9(11):1397.PubMedCrossRefGoogle Scholar
  18. 18.
    Olesen S-P, Clapham DE, Davies PF. Hemodynamic shear stress activates a K+ current in vascular endothelial cells. Nature. 1988;331(6152):168–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Davies PF. Flow-mediated endothelial mechanotransduction. Physiol Rev. 1995;75:519–60.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Fang Y, Schram G, Romanenko VG, Shi C, Conti L, Vandenberg CA, et al. Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2. Am J Physiol Cell Physiol. 2005;289(5):C1134–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Ahn SJ, Fancher IS, Bian J-T, Zhang CX, Schwab S, Gaffin R, et al. Inwardly rectifying K+ channels are major contributors to flow-induced vasodilatation in resistance arteries. J Physiol. 2017;595(7):2339–64.PubMedCrossRefGoogle Scholar
  22. 22.
    Fancher IS, Ahn SJ, Adamos C, Osborn C, Oh M-J, Fang Y, et al. Hypercholesterolemia-induced loss of flow-induced vasodilation and lesion formation in apolipoprotein E-deficient mice critically depend on inwardly rectifying K+ channels. J Am Heart Assoc. 2018;7(5):e007430.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Barbera N, Ayee MAA, Akpa BS, Levitan I. Differential effects of sterols on ion channels: stereospecific binding vs stereospecific response. Curr Top Membr. 2017;80:25–52.PubMedCrossRefGoogle Scholar
  24. 24.
    Sooksawate T, Simmonds M. Effects of membrane cholesterol on the sensitivity of the GABAA receptor to GABA in acutely dissociated rat hippocampal neurones. Neuropharmacology. 2001;40(2):178–84.PubMedCrossRefGoogle Scholar
  25. 25.
    Sigel E, Steinmann ME. Structure, function, and modulation of GABAA receptors. J Biol Chem. 2012;287(48):40224–31.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Romanenko VG, Fang Y, Byfield F, Travis AJ, Vandenberg CA, Rothblat GH, et al. Cholesterol sensitivity and lipid raft targeting of Kir2. 1 channels. Biophys J. 2004;87(6):3850–61.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Tikku S, Epshtein Y, Collins H, Travis AJ, Rothblat GH, Levitan I. Relationship between Kir2. 1/Kir2. 3 activity and their distributions between cholesterol-rich and cholesterol-poor membrane domains. Am J Phys Cell Phys. 2007;293(1):C440–C50.CrossRefGoogle Scholar
  28. 28.
    Han H, Rosenhouse-Dantsker A, Gnanasambandam R, Epshtein Y, Chen Z, Sachs F, et al. Silencing of Kir2 channels by caveolin-1: cross-talk with cholesterol. J Physiol. 2014;592(18):4025–38.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Fang Y, Shaffer RG, Moore J, Mohler E, Levitan I. Hypercholesterolemia alters the functional properties of inwardly-rectifying K channels in side-population endothelial progenitor cells in a pig model. Vasc Pharmacol. 2006;45(3):e28–e9.CrossRefGoogle Scholar
  30. 30.
    Zidovetzki R, Levitan I. Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies. Biochim Biophys Acta Biomembr. 2007;1768(6):1311.CrossRefGoogle Scholar
  31. 31.
    Fang Y, Schram G, Romanenko VG, Shi C, Conti L, Vandenberg CA, et al. Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2. Am J Phys Cell Phys. 2005;289(5):C1134–C44.CrossRefGoogle Scholar
  32. 32.
    Rosenhouse-Dantsker A, Leal-Pinto E, Logothetis DE, Levitan I. Comparative analysis of cholesterol sensitivity of Kir channels: role of the CD loop. Channels. 2010;4(1):63–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Deng W, Bukiya AN, Rodríguez-Menchaca AA, Zhang Z, Baumgarten CM, Logothetis DE, et al. Hypercholesterolemia induces up-regulation of KACh cardiac currents via a mechanism independent of phosphatidylinositol 4,5-bisphosphate and Gβγ. J Biol Chem. 2012;287(7):4925–35.PubMedCrossRefGoogle Scholar
  34. 34.
    Bukiya AN, Durdagi S, Noskov S, Rosenhouse-Dantsker A. Cholesterol up-regulates neuronal G protein-gated inwardly rectifying potassium (GIRK) channel activity in the hippocampus. J Biol Chem. 2017;292(15):6135–47.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Epshtein Y, Chopra AP, Rosenhouse-Dantsker A, Kowalsky GB, Logothetis DE, Levitan I. Identification of a C-terminus domain critical for the sensitivity of Kir2. 1 to cholesterol. Proc Natl Acad Sci. 2009;106(19):8055–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Singh DK, Rosenhouse-Dantsker A, Nichols CG, Enkvetchakul D, Levitan I. Direct regulation of prokaryotic Kir channel by cholesterol. J Biol Chem. 2009;284(44):30727–36.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    D’Avanzo N, Hyrc K, Enkvetchakul D, Covey DF, Nichols CG. Enantioselective protein-sterol interactions mediate regulation of both prokaryotic and eukaryotic inward rectifier K+ channels by cholesterol. PLoS One. 2011;6(4):e19393.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Chang H, Reitstetter R, Mason R, Gruener R. Attenuation of channel kinetics and conductance by cholesterol: an interpretation using structural stress as a unifying concept. J Membr Biol. 1995;143(1):51–63.PubMedCrossRefGoogle Scholar
  39. 39.
    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.PubMedCrossRefGoogle Scholar
  40. 40.
    Dopico AM, Bukiya AN. Regulation of Ca2+-sensitive K+ channels by cholesterol and bile acids via distinct channel subunits and sites. Curr Top Membr. 2017;80:53–94.PubMedCrossRefGoogle Scholar
  41. 41.
    Morales-Lázaro SL, Rosenbaum T. Multiple mechanisms of regulation of transient receptor potential ion channels by cholesterol. Curr Top Membr. 2017;80:139–62.PubMedCrossRefGoogle Scholar
  42. 42.
    Peters M, Katz B, Lev S, Zaguri R, Gutorov R, Minke B. Depletion of membrane cholesterol suppresses drosophila transient receptor potential-like (TRPL) channel activity. Curr Top Membr. 2017;80:233–54.PubMedCrossRefGoogle Scholar
  43. 43.
    Di Scala C, Baier CJ, Evans LS, Williamson PTF, Fantini J, Barrantes FJ. Relevance of CARC and CRAC cholesterol-recognition motifs in the nicotinic acetylcholine receptor and other membrane-bound receptors. Curr Top Membr. 2017;80:3–24.PubMedCrossRefGoogle Scholar
  44. 44.
    Baenziger JE, Domville JA, Therien JD. The role of cholesterol in the activation of nicotinic acetylcholine receptors. Curr Top Membr. 2017;80:95–137.PubMedCrossRefGoogle Scholar
  45. 45.
    Corbin J, Wang HH, Blanton MP. Identifying the cholesterol binding domain in the nicotinic acetylcholine receptor with [125 I] azido-cholesterol. Biochim Biophys Acta Biomembr. 1998;1414(1):65–74.CrossRefGoogle Scholar
  46. 46.
    Hamouda AK, Chiara DC, Sauls D, Cohen JB, Blanton MP. Cholesterol interacts with transmembrane α-helices M1, M3, and M4 of the Torpedo nicotinic acetylcholine receptor: photolabeling studies using [3H] azicholesterol. Biochemistry. 2006;45(3):976–86.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Syeda R, Qiu Z, Dubin AE, Murthy SE, Florendo MN, Mason DE, et al. LRRC8 proteins form volume-regulated anion channels that sense ionic strength. Cell. 2016;164(3):499–511.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Fantini J, Barrantes FJ. How cholesterol interacts with membrane proteins: an exploration of cholesterol-binding sites including CRAC, CARC, and tilted domains. Front Physiol. 2013;4:31.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola V-P, Chien EY, et al. A specific cholesterol binding site is established by the 2.8 Å structure of the human β2-adrenergic receptor. Structure. 2008;16(6):897–905.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Singh AK, McMillan J, Bukiya AN, Burton B, Parrill AL, Dopico AM. Multiple cholesterol recognition/interaction amino acid consensus (CRAC) motifs in cytosolic C tail of Slo1 subunit determine cholesterol sensitivity of Ca2+-and voltage-gated K+ (BK) channels. J Biol Chem. 2012;287(24):20509–21.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Balajthy A, Hajdu P, Panyi G, Varga Z. Sterol regulation of voltage-gated K+ channels. Curr Top Membr. 2017;80:255–91.PubMedCrossRefGoogle Scholar
  52. 52.
    Murell-Lagnado RD. Regulation of P2X purinergic receptor signaling by cholesterol. Curr Top Membr. 2017;80:211–32.CrossRefGoogle Scholar
  53. 53.
    Rosenhouse-Dantsker A, Noskov S, Durdagi S, Logothetis DE, Levitan I. Identification of novel cholesterol-binding regions in Kir2 channels. J Biol Chem. 2013;288(43):31154–64.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Nishida M, Cadene M, Chait BT, MacKinnon R. Crystal structure of a Kir3.1-prokaryotic Kir channel chimera. EMBO J. 2007;26(17):4005–15.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Fürst O, Nichols CG, Lamoureux G, D’Avanzo N. Identification of a cholesterol-binding pocket in inward rectifier K+(Kir) channels. Biophys J. 2014;107(12):2786–96.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Rosenhouse-Dantsker A. Insights into the molecular requirements for cholesterol binding to ion channels. Curr Top Membr. 2017;80:187–210.PubMedCrossRefGoogle Scholar
  57. 57.
    Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov. 2004;3(11):935.PubMedCrossRefGoogle Scholar
  58. 58.
    Huang S-Y, Zou X. Advances and challenges in protein-ligand docking. Int J Mol Sci. 2010;11(8):3016–34.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Chaudhary KK, Mishra N. A review on molecular docking: novel tool for drug discovery. Database. 2016;3:4.Google Scholar
  60. 60.
    de Ruyck J, Brysbaert G, Blossey R, Lensink MF. Molecular docking as a popular tool in drug design, an in silico travel. Adv Appl Bioinforma Chem. 2016;9:1.Google Scholar
  61. 61.
    Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785–91.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Pulmonary and Critical Care, Department of MedicineUniversity of Illinois at ChicagoChicagoUSA

Personalised recommendations