Advertisement

A Critical Analysis of Molecular Mechanisms Underlying Membrane Cholesterol Sensitivity of GPCRs

  • Md. Jafurulla
  • G. Aditya Kumar
  • Bhagyashree D. Rao
  • Amitabha ChattopadhyayEmail author
Chapter
First Online:
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1115)

Abstract

G protein-coupled receptors (GPCRs) are the largest and a diverse family of proteins involved in signal transduction across biological membranes. GPCRs mediate a wide range of physiological processes and have emerged as major targets for the development of novel drug candidates in all clinical areas. Since GPCRs are integral membrane proteins, regulation of their organization, dynamics, and function by membrane lipids, in particular membrane cholesterol, has emerged as an exciting area of research. Cholesterol sensitivity of GPCRs could be due to direct interaction of cholesterol with the receptor (specific effect). Alternately, GPCR function could be influenced by the effect of cholesterol on membrane physical properties (general effect). In this review, we critically analyze the specific and general mechanisms of the modulation of GPCR function by membrane cholesterol, taking examples from representative GPCRs. While evidence for both the proposed mechanisms exists, there appears to be no clear-cut distinction between these two mechanisms, and a combination of these mechanisms cannot be ruled out in many cases. We conclude that classifying the mechanism underlying cholesterol sensitivity of GPCR function merely into these two mutually exclusive classes could be somewhat arbitrary. A more holistic approach could be suitable for analyzing GPCR–cholesterol interaction.

Keywords

GPCR–cholesterol interaction Specific effect General effect Cholesterol binding motifs 

Abbreviations

7-DHC

7-Dehydrocholesterol

7-DHCR

3β-Hydroxy-steroid-Δ7-reductase

24-DHCR

3β-Hydroxy-steroid-Δ24-reductase

AY 9944

trans-1,4-bis(2-chlorobenzylaminoethyl)cyclohexane dihydrochloride

CB

Cannabinoid receptor

CCK

Cholecystokinin receptor

CCM

Cholesterol consensus motif

CCR5

CC chemokine receptor 5

CRAC

Cholesterol recognition/interaction amino acid consensus

CXCR4

CXC chemokine receptor 4

GalR2

Galanin receptor 2

GPCR

G protein-coupled receptor

MβCD

Methyl-β-cyclodextrin

MI

Metarhodopsin I

MII

Metarhodopsin II

mGluR

Metabotropic glutamate receptor

SLOS

Smith–Lemli–Opitz syndrome

Smo

Smoothened

T2R4

Bitter taste receptor 4

This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

A.C. gratefully acknowledges support from SERB Distinguished Fellowship (Department of Science and Technology, Govt. of India). G.A.K. and B.D.R. thank the Council of Scientific and Industrial Research and University Grants Commission for the award of Senior Research Fellowships, respectively. A.C. is a Distinguished Visiting Professor at Indian Institute of Technology, Bombay (Mumbai), and Adjunct Professor at Tata Institute of Fundamental Research (Mumbai), RMIT University (Melbourne, Australia), and Indian Institute of Science Education and Research (Kolkata). Some of the work described in this article was carried out by former members of A.C.’s research group whose contributions are gratefully acknowledged. We thank members of the Chattopadhyay laboratory, particularly Parijat Sarkar, for comments and discussions.

References

  1. 1.
    Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptors. Nat Rev Mol Cell Biol. 2002;3:639–50.PubMedCrossRefGoogle Scholar
  2. 2.
    Rosenbaum DM, Rasmussen SGF, Kobilka BK. The structure and function of G-protein-coupled receptors. Nature. 2009;459:356–63.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Chattopadhyay A. GPCRs: lipid-dependent membrane receptors that act as drug targets. Adv Biol. 2014;2014:143023.CrossRefGoogle Scholar
  4. 4.
    Zhang Y, DeVries ME, Skolnick J. Structure modeling of all identified G protein-coupled receptors in the human genome. PLoS Comput Biol. 2006;2:e13.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Gether U. Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr Rev. 2000;21:90–113.PubMedCrossRefGoogle Scholar
  6. 6.
    Weis WI, Kobilka BK. The molecular basis of G protein-coupled receptor activation. Annu Rev Biochem. 2018;87:897–919.PubMedCrossRefGoogle Scholar
  7. 7.
    Heilker R, Wolff M, Tautermann CS, Bieler M. G-protein-coupled receptor-focused drug discovery using a target class platform approach. Drug Discov Today. 2009;14:231–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Cooke RM, Brown AJH, Marshall FH, Mason JS. Structures of G protein-coupled receptors reveal new opportunities for drug discovery. Drug Discov Today. 2015;20:1355–64.PubMedCrossRefGoogle Scholar
  9. 9.
    Jacobson KA. New paradigms in GPCR drug discovery. Biochem Pharmacol. 2015;98:541–55.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Kumari P, Ghosh E, Shukla AK. Emerging approaches to GPCR ligand screening for drug discovery. Trends Mol Med. 2015;21:687–701.PubMedCrossRefGoogle Scholar
  11. 11.
    Gutierrez AN, McDonald PH. GPCRs: emerging anti-cancer drug targets. Cell Signal. 2018;41:65–74.CrossRefGoogle Scholar
  12. 12.
    Thomsen W, Frazer J, Unett D. Functional assays for screening GPCR targets. Curr Opin Biotechnol. 2005;16:655–65.PubMedGoogle Scholar
  13. 13.
    Schlyer S, Horuk R. I want a new drug: G-protein-coupled receptors in drug development. Drug Discov Today. 2006;11:481–93.PubMedCrossRefGoogle Scholar
  14. 14.
    Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov. 2017;16:829–42.PubMedCrossRefGoogle Scholar
  15. 15.
    Lin SHS, Civelli O. Orphan G protein-coupled receptors: targets for new therapeutic interventions. Ann Med. 2004;36:204–14.PubMedCrossRefGoogle Scholar
  16. 16.
    Stockert JA, Devi LA. Advancements in therapeutically targeting orphan GPCRs. Front Pharmacol. 2015;6:100.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Huber T, Botelho AV, Beyer K, Brown MF. Membrane model for the G-protein-coupled receptor rhodopsin: hydrophobic interface and dynamical structure. Biophys J. 2004;86:2078–100.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    van Meer G, Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008;9:112–24.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    van Meer G, de Kroon AIPM. Lipid map of the mammalian cell. J Cell Sci. 2011;124:5–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Brown AJ, Galea AM. Cholesterol as an evolutionary response to living with oxygen. Evolution. 2010;64:2179–83.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Kumar GA, Chattopadhyay A. Cholesterol: an evergreen molecule in biology. Biomed Spectrosc Imaging. 2016;5:S55–66.CrossRefGoogle Scholar
  22. 22.
    Chaudhuri A, Chattopadhyay A. Transbilayer organization of membrane cholesterol at low concentrations: implications in health and disease. Biochim Biophys Acta. 2011;1808:19–25.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Fantini J, Barrantes FJ. Sphingolipid/cholesterol regulation of neurotransmitter receptor conformation and function. Biochim Biophys Acta. 2009;1788:2345–61.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    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
  25. 25.
    Simons K, Ikonen E. How cells handle cholesterol. Science. 2000;290:1721–6.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Mukherjee S, Maxfield FR. Membrane domains. Annu Rev Cell Dev Biol. 2004;20:839–66.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Lingwood D, Simons K. Lipid rafts as a membrane organizing principle. Science. 2010;327:46–50.PubMedCrossRefGoogle Scholar
  29. 29.
    Simons K, van Meer G. Lipid sorting in epithelial cells. Biochemistry. 1988;27:6197–202.PubMedCrossRefGoogle Scholar
  30. 30.
    Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000;1:31–9.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    van der Goot FG, Harder T. Raft membrane domains: from a liquid-ordered membrane phase to a site of pathogen attack. Semin Immunol. 2001;13:89–97.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Pucadyil TJ, Chattopadhyay A. Cholesterol: a potential therapeutic target in Leishmania infection? Trends Parasitol. 2007;23:49–53.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Vieira FS, Corrêa G, Einicker-Lamas M, Coutinho-Silva R. Host-cell lipid rafts: a safe door for micro-organisms? Biol Cell. 2010;102:391–407.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Chattopadhyay A, Jafurulla M. Role of membrane cholesterol in leishmanial infection. Adv Exp Med Biol. 2012;749:201–13.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Kumar GA, Jafurulla M, Chattopadhyay A. The membrane as the gatekeeper of infection: cholesterol in host-pathogen interaction. Chem Phys Lipids. 2016;199:179–85.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Pucadyil TJ, Chattopadhyay A. Role of cholesterol in the function and organization of G-protein coupled receptors. Prog Lipid Res. 2006;45:295–333.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Paila YD, Chattopadhyay A. Membrane cholesterol in the function and organization of G-protein coupled receptors. Subcell Biochem. 2010;51:439–66.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Oates J, Watts A. Uncovering the intimate relationship between lipids, cholesterol and GPCR activation. Curr Opin Struct Biol. 2011;21:802–7.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Jafurulla M, Chattopadhyay A. Membrane lipids in the function of serotonin and adrenergic receptors. Curr Med Chem. 2013;20:47–55.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Sengupta D, Chattopadhyay A. Molecular dynamics simulations of GPCR-cholesterol interaction: an emerging paradigm. Biochim Biophys Acta. 2015;1848:1775–82.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Gimpl G. Interaction of G protein coupled receptors and cholesterol. Chem Phys Lipids. 2016;199:61–73.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Sengupta D, Prasanna X, Mohole M, Chattopadhyay A. Exploring GPCR-lipid interactions by molecular dynamics simulations: excitements, challenges and the way forward. J Phys Chem B. 2018;122:5727–37.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Paila YD, Murty MRVS, Vairamani M, Chattopadhyay A. Signaling by the human serotonin1A receptor is impaired in cellular model of Smith–Lemli–Opitz syndrome. Biochim Biophys Acta. 2008;1778:1508–16.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol. 2001;12:105–12.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Chattopadhyay A, Paila YD. Lipid-protein interactions, regulation and dysfunction of brain cholesterol. Biochem Biophys Res Commun. 2007;354:627–33.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Martin M, Dotti CG, Ledesma MD. Brain cholesterol in normal and pathological aging. Biochim Biophys Acta. 2010;1801:934–44.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Karnell FG, Brezski RJ, King LG, Silverman MA, Monroe JG. Membrane cholesterol content accounts for developmental differences in surface B cell receptor compartmentalization and signaling. J Biol Chem. 2005;280:25621–8.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Paila YD, Chattopadhyay A. The function of G-protein coupled receptors and membrane cholesterol: specific or general interaction? Glycoconj J. 2009;26:711–20.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Paila YD, Tiwari S, Chattopadhyay A. Are specific nonannular cholesterol binding sites present in G-protein coupled receptors? Biochim Biophys Acta. 2009;1788:295–302.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Seddon AM, Curnow P, Booth PJ. Membrane proteins, lipids and detergents: not just a soap opera. Biochim Biophys Acta. 2004;1666:105–17.PubMedCrossRefGoogle Scholar
  51. 51.
    Kalipatnapu S, Chattopadhyay A. Membrane protein solubilization: recent advances and challenges in solubilization of serotonin1A receptors. IUBMB Life. 2005;57:505–12.PubMedCrossRefGoogle Scholar
  52. 52.
    Privé GG. Detergents for the stabilization and crystallization of membrane proteins. Methods. 2007;41:388–97.PubMedCrossRefGoogle Scholar
  53. 53.
    Duquesne K, Sturgis JN. Membrane protein solubilization. Methods Mol Biol. 2010;601:205–17.PubMedCrossRefGoogle Scholar
  54. 54.
    Chattopadhyay A, Rao BD, Jafurulla M. Solubilization of G protein-coupled receptors: a convenient strategy to explore lipid-receptor interaction. Methods Enzymol. 2015;557:117–34.PubMedCrossRefGoogle Scholar
  55. 55.
    Goddard AD, Dijkman PM, Adamson RJ, dos Reis RI, Watts A. Reconstitution of membrane proteins: a GPCR as an example. Methods Enzymol. 2015;556:405–24.PubMedCrossRefGoogle Scholar
  56. 56.
    Serebryany E, Zhu GA, Yan ECY. Artificial membrane-like environments for in vitro studies of purified G-protein coupled receptors. Biochim Biophys Acta. 2012;1818:225–33.PubMedCrossRefGoogle Scholar
  57. 57.
    Chattopadhyay A, Jafurulla M, Kalipatnapu S, Pucadyil TJ, Harikumar KG. Role of cholesterol in ligand binding and G-protein coupling of serotonin1A receptors solubilized from bovine hippocampus. Biochem Biophys Res Commun. 2005;327:1036–41.PubMedCrossRefGoogle Scholar
  58. 58.
    Chattopadhyay A, Paila YD, Jafurulla M, Chaudhuri A, Singh P, Murty MRVS, et al. Differential effects of cholesterol and 7-dehydrocholesterol on ligand binding of solubilized hippocampal serotonin1A receptors: implications in SLOS. Biochem Biophys Res Commun. 2007;363:800–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Singh P, Jafurulla M, Paila YD, Chattopadhyay A. Desmosterol replaces cholesterol for ligand binding function of the serotonin1A receptor in solubilized hippocampal membranes: support for nonannular binding sites for cholesterol? Biochim Biophys Acta. 2011;1808:2428–34.PubMedCrossRefGoogle Scholar
  60. 60.
    Jafurulla M, Rao BD, Sreedevi S, Ruysschaert J-M, Covey DF, Chattopadhyay A. Stereospecific requirement of cholesterol in the function of the serotonin1A receptor. Biochim Biophys Acta. 2014;1838:158–63.PubMedCrossRefGoogle Scholar
  61. 61.
    Nes WD. Biosynthesis of cholesterol and other sterols. Chem Rev. 2011;111:6423–51.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Levitt ES, Clark MJ, Jenkins PM, Martens JR, Traynor JR. Differential effect of membrane cholesterol removal on μ- and δ-opioid receptors: a parallel comparison of acute and chronic signaling to adenylyl cyclase. J Biol Chem. 2009;284:22108–22.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Shrivastava S, Pucadyil TJ, Paila YD, Ganguly S, Chattopadhyay A. Chronic cholesterol depletion using statin impairs the function and dynamics of human serotonin1A receptors. Biochemistry. 2010;49:5426–35.PubMedCrossRefGoogle Scholar
  64. 64.
    Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292:1160–4.CrossRefGoogle Scholar
  65. 65.
    Mizuno GR, Chapman CJ, Chipault JR, Pfeiffer DR. Lipid composition and (Na++K+)-ATPase activity in rat lens during triparanol-induced cataract formation. Biochim Biophys Acta. 1981;644:1–12.PubMedCrossRefGoogle Scholar
  66. 66.
    Kolf-Clauw M, Chevy F, Wolf C, Siliart B, Citadelle D, Roux C. Inhibition of 7-dehydrocholesterol reductase by the teratogen AY9944: a rat model for Smith-Lemli-Opitz syndrome. Teratology. 1996;54:115–25.PubMedCrossRefGoogle Scholar
  67. 67.
    Kandutsch AA, Russell AE. Preputial gland tumor sterols. A metabolic pathway from lanosterol to cholesterol. J Biol Chem. 1960;235:2256–61.PubMedGoogle Scholar
  68. 68.
    Bloch KE. Sterol structure and membrane function. CRC Crit Rev Biochem. 1983;14:47–92.PubMedCrossRefGoogle Scholar
  69. 69.
    Porter FD, Herman GE. Malformation syndromes caused by disorders of cholesterol synthesis. J Lipid Res. 2011;52:6–34.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Kanungo S, Soares N, He M, Steiner RD. Sterol metabolism disorders and neurodevelopment-an update. Dev Disabil Res Rev. 2013;17:197–210.PubMedCrossRefGoogle Scholar
  71. 71.
    Gaoua W, Wolf C, Chevy F, Ilien F, Roux C. Cholesterol deficit but not accumulation of aberrant sterols is the major cause of the teratogenic activity in the Smith-Lemli-Opitz syndrome animal model. J Lipid Res. 2000;41:637–46.PubMedGoogle Scholar
  72. 72.
    Chevy F, Illien F, Wolf C, Roux C. Limb malformations of rat fetuses exposed to a distal inhibitor of cholesterol biosynthesis. J Lipid Res. 2002;43:1192–200.PubMedGoogle Scholar
  73. 73.
    Zidovetzki R, Levitan I. Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies. Biochim Biophys Acta. 2007;1768:1311–24.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    López CA, de Vries AH, Marrink SJ. Computational microscopy of cyclodextrin mediated cholesterol extraction from lipid model membranes. Sci Rep. 2013;3:2071.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Niu S-L, Mitchell DC, Litman BJ. Manipulation of cholesterol levels in rod disk membranes by methyl-β-cyclodextrin: effects on receptor activation. J Biol Chem. 2002;277:20139–45.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Gimpl G, Burger K, Fahrenholz F. Cholesterol as modulator of receptor function. Biochemistry. 1997;36:10959–74.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Pang L, Graziano M, Wang S. Membrane cholesterol modulates galanin-GalR2 interaction. Biochemistry. 1999;38:12003–11.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Pucadyil TJ, Chattopadhyay A. Cholesterol modulates ligand binding and G-protein coupling to serotonin1A receptors from bovine hippocampus. Biochim Biophys Acta. 2004;1663:188–200.PubMedCrossRefGoogle Scholar
  79. 79.
    Pucadyil TJ, Chattopadhyay A. Cholesterol depletion induces dynamic confinement of the G-protein coupled serotonin1A receptor in the plasma membrane of living cells. Biochim Biophys Acta. 2007;1768:655–68.PubMedCrossRefGoogle Scholar
  80. 80.
    Bari M, Battista N, Fezza F, Finazzi-Agrò A, Maccarrone M. Lipid rafts control signaling of type-1 cannabinoid receptors in neuronal cells. Implications for anandamide-induced apoptosis. J Biol Chem. 2005;280:12212–20.CrossRefGoogle Scholar
  81. 81.
    Bari M, Paradisi A, Pasquariello N, Maccarrone M. Cholesterol-dependent modulation of type 1 cannabinoid receptors in nerve cells. J Neurosci Res. 2005;81:275–83.PubMedCrossRefGoogle Scholar
  82. 82.
    Bari M, Spagnuolo P, Fezza F, Oddi S, Pasquariello N, Finazzi-Agrò A, et al. Effect of lipid rafts on Cb2 receptor signaling and 2-arachidonoyl-glycerol metabolism in human immune cells. J Immunol. 2006;177:4971–80.PubMedCrossRefGoogle Scholar
  83. 83.
    Pydi SP, Jafurulla M, Wai L, Bhullar RP, Chelikani P, Chattopadhyay A. Cholesterol modulates bitter taste receptor function. Biochim Biophys Acta. 2016;1858:2081–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Chattopadhyay A, Jafurulla M, Pucadyil TJ. Ligand binding and G-protein coupling of the serotonin1A receptor in cholesterol-enriched hippocampal membranes. Biosci Rep. 2006;26:79–87.PubMedCrossRefGoogle Scholar
  85. 85.
    Sarkar P, Chakraborty H, Chattopadhyay A. Differential membrane dipolar orientation induced by acute and chronic cholesterol depletion. Sci Rep. 2017;7:4484.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Sampson NS, Vrielink A. Cholesterol oxidases: a study of nature’s approach to protein design. Acc Chem Res. 2003;36:713–22.PubMedCrossRefGoogle Scholar
  87. 87.
    Pucadyil TJ, Shrivastava S, Chattopadhyay A. Membrane cholesterol oxidation inhibits ligand binding function of hippocampal serotonin1A receptors. Biochem Biophys Res Commun. 2005;331:422–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Jafurulla M, Nalli A, Chattopadhyay A. Membrane cholesterol oxidation in live cells enhances the function of serotonin1A receptors. Chem Phys Lipids. 2017;203:71–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Boesze-Battaglia K, Albert AD. Cholesterol modulation of photoreceptor function in bovine retinal rod outer segments. J Biol Chem. 1990;265:20727–30.PubMedGoogle Scholar
  90. 90.
    Nguyen DH, Taub D. Inhibition of chemokine receptor function by membrane cholesterol oxidation. Exp Cell Res. 2003;291:36–45.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Holz RW. The effects of the polyene antibiotics nystatin and amphotericin B on thin lipid membranes. Ann N Y Acad Sci. 1974;235:469–79.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Nishikawa M, Nojima S, Akiyama T, Sankawa U, Inoue K. Interaction of digitonin and its analogs with membrane cholesterol. J Biochem. 1984;96:1231–9.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Bolard J. How do the polyene macrolide antibiotics affect the cellular membrane properties? Biochim Biophys Acta. 1986;864:257–304.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Coutinho A, Prieto M. Cooperative partition model of nystatin interaction with phospholipid vesicles. Biophys J. 2003;84:3061–78.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Savinov SN, Heuck AP. Interaction of cholesterol with perfringolysin O: what have we learned from functional analysis? Toxins. 2017;9:381.PubMedCentralCrossRefGoogle Scholar
  96. 96.
    Pucadyil TJ, Shrivastava S, Chattopadhyay A. The sterol-binding antibiotic nystatin differentially modulates ligand binding of the bovine hippocampal serotonin1A receptor. Biochem Biophys Res Commun. 2004;320:557–62.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Paila YD, Pucadyil TJ, Chattopadhyay A. The cholesterol-complexing agent digitonin modulates ligand binding of the bovine hippocampal serotonin1A receptor. Mol Membr Biol. 2005;22:241–9.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Pucadyil TJ, Kalipatnapu S, Chattopadhyay A. The serotonin1A receptor: a representative member of the serotonin receptor family. Cell Mol Neurobiol. 2005;25:553–80.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Kalipatnapu S, Chattopadhyay A. Membrane organization and function of the serotonin1A receptor. Cell Mol Neurobiol. 2007;27:1097–116.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Müller CP, Carey RJ, Huston JP, De Souza Silva MA. Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors. Prog Neurobiol. 2007;81:133–78.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Lacivita E, Leopoldo M, Berardi F, Perrone R. 5-HT1A receptor, an old target for new therapeutic agents. Curr Top Med Chem. 2008;8:1024–34.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Fiorino F, Severino B, Magli E, Ciano A, Caliendo G, Santagada V, et al. 5-HT1A receptor: an old target as a new attractive tool in drug discovery from central nervous system to cancer. J Med Chem. 2014;57:4407–26.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Singh P, Paila YD, Chattopadhyay A. Differential effects of cholesterol and 7-dehydrocholesterol on the ligand binding activity of the hippocampal serotonin1A receptor: implications in SLOS. Biochem Biophys Res Commun. 2007;358:495–9.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Saxena R, Chattopadhyay A. Membrane cholesterol stabilizes the human serotonin1A receptor. Biochim Biophys Acta. 2012;1818:2936–42.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Paila YD, Tiwari S, Sengupta D, Chattopadhyay A. Molecular modeling of the human serotonin1A receptor: role of membrane cholesterol in ligand binding of the receptor. Mol BioSyst. 2011;7:224–34.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Patra SM, Chakraborty S, Shahane G, Prasanna X, Sengupta D, Maiti PK, et al. Differential dynamics of the serotonin1A receptor in membrane bilayers of varying cholesterol content revealed by all atom molecular dynamics simulation. Mol Membr Biol. 2015;32:127–37.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Burger K, Gimpl G, Fahrenholz F. Regulation of receptor function by cholesterol. Cell Mol Life Sci. 2000;57:1577–92.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Klein U, Gimpl G, Fahrenholz F. Alteration of the myometrial plasma membrane cholesterol content with β-cyclodextrin modulates the binding affinity of the oxytocin receptor. Biochemistry. 1995;34:13784–93.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Gimpl G, Fahrenholz F. Cholesterol as stabilizer of the oxytocin receptor. Biochim Biophys Acta. 2002;1564:384–92.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Nguyen DH, Taub D. Cholesterol is essential for macrophage inflammatory protein 1 beta binding and conformational integrity of CC chemokine receptor 5. Blood. 2002;99:4298–306.PubMedCrossRefGoogle Scholar
  111. 111.
    Nguyen DH, Taub D. CXCR4 function requires membrane cholesterol: implications for HIV infection. J Immunol. 2002;168:4121–6.PubMedCrossRefGoogle Scholar
  112. 112.
    Behrens M, Meyerhof W. Bitter taste receptors and human bitter taste perception. Cell Mol Life Sci. 2006;63:1501–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Oddi S, Dainese E, Fezza F, Lanuti M, Barcaroli D, De Laurenzi V, et al. Functional characterization of putative cholesterol binding sequence (CRAC) in human type-1 cannabinoid receptor. J Neurochem. 2011;116:858–65.PubMedCrossRefGoogle Scholar
  114. 114.
    Harikumar KG, Puri V, Singh RD, Hanada K, Pagano RE, Miller LJ. Differential effects of modification of membrane cholesterol and sphingolipids on the conformation, function, and trafficking of the G protein-coupled cholecystokinin receptor. J Biol Chem. 2005;280:2176–85.PubMedCrossRefGoogle Scholar
  115. 115.
    Potter RM, Harikumar KG, Wu SV, Miller LJ. Differential sensitivity of types 1 and 2 cholecystokinin receptors to membrane cholesterol. J Lipid Res. 2012;53:137–48.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS, et al. High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science. 2007;318:1258–65.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola V-P, Chein YET, et al. A specific cholesterol binding site is established by the 2.8 Å structure of the human β2-adrenergic receptor. Structure. 2008;16:897–905.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Wacker D, Fenalti G, Brown MA, Katritch V, Abagyan R, Cherezov V, et al. Conserved binding mode of human β 2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography. J Am Chem Soc. 2010;132:11443–5.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, Arlow DH, et al. Structure and function of an irreversible agonist-β2 adrenoceptor complex. Nature. 2011;469:236–40.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Staus DP, Strachan RT, Manglik A, Pani B, Kahsai AW, Kim TH, et al. Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation. Nature. 2016;535:448–52.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Huang C-Y, Olieric V, Ma P, Howe N, Vogeley L, Liu X, et al. In meso in situ serial X-ray crystallography of soluble and membrane proteins at cryogenic temperatures. Acta Crystallogr D Struct Biol. 2016;72:93–112.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Liu X, Ahn S, Kahsai AW, Meng K-C, Latorraca NR, Pani B, et al. Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure. Nature. 2017;548:480–4.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Ma P, Weichert D, Aleksandrov LA, Jensen TJ, Riordan JR, Liu X, et al. The cubicon method for concentrating membrane proteins in the cubic mesophase. Nat Protoc. 2017;12:1745–62.PubMedCrossRefGoogle Scholar
  124. 124.
    Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, et al. Structural basis for allosteric regulation of GPCRs by sodium ions. Science. 2012;337:232–6.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Batyuk A, Galli L, Ishchenko A, Han GW, Gati C, Popov PA, et al. Native phasing of x-ray free-electron laser data for a G protein-coupled receptor. Sci Adv. 2016;2:e1600292.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Segala E, Guo D, Cheng RKY, Bortolato A, Deflorian F, Doré AS, et al. Controlling the dissociation of ligands from the adenosine A2A receptor through modulation of salt bridge strength. J Med Chem. 2016;59:6470–9.PubMedCrossRefGoogle Scholar
  127. 127.
    Martin-Garcia JM, Conrad CE, Nelson G, Stander N, Zatsepin NA, Zook J, et al. Serial millisecond crystallography of membrane and soluble protein microcrystals using synchrotron radiation. IUCrJ. 2017;4:439–54.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Weinert T, Olieric N, Cheng R, Brünle S, James D, Ozerov D, et al. Serial millisecond crystallography for routine room-temperature structure determination at synchrotrons. Nat Commun. 2017;8:542.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Cheng RKY, Segala E, Robertson N, Deflorian F, Doré AS, Errey JC, et al. Structures of human A1 and A2A adenosine receptors with xanthines reveal determinants of selectivity. Structure. 2017;25:1275–85.PubMedCrossRefGoogle Scholar
  130. 130.
    Melnikov I, Polovinkin V, Kovalev K, Gushchin I, Shevtsov M, Shevchenko V, et al. Fast iodide-SAD phasing for high-throughput membrane protein structure determination. Sci Adv. 2017;3:e1602952.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Broecker J, Morizumi T, Ou W-L, Klingel V, Kuo A, Kissick DJ, et al. High-throughput in situ X-ray screening of and data collection from protein crystals at room temperature and under cryogenic conditions. Nat Protoc. 2018;13:260–92.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Eddy MT, Lee M-Y, Gao Z-G, White KL, Didenko T, Horst R, et al. Allosteric coupling of drug binding and intracellular signaling in the A2A adenosine receptor. Cell. 2018;172:68–80.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Rucktooa P, Cheng RKY, Segala E, Geng T, Errey JC, Brown GA, et al. Towards high throughput GPCR crystallography: in meso soaking of adenosine A2A receptor crystals. Sci Rep. 2018;8:41.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Che T, Majumdar S, Zaidi SA, Ondachi P, McCorvy JD, Wang S, et al. Structure of the nanobody-stabilized active state of the kappa opioid receptor. Cell. 2018;172:55–67.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, et al. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature. 2012;485:321–6.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, et al. Structural insights into μ-opioid receptor activation. Nature. 2015;524:315–21.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, et al. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science. 2014;344:58–64.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Byrne EFX, Sircar R, Miller PS, Hedger G, Luchetti G, Nachtergaele S, et al. Structural basis of smoothened regulation by its extracellular domains. Nature. 2016;535:517–22.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Huang P, Zheng S, Wierbowski BM, Kim Y, Nedelcu D, Aravena L, et al. Structural basis of smoothened activation in hedgehog signaling. Cell. 2018;174:1–13.CrossRefGoogle Scholar
  140. 140.
    Wacker D, Wang C, Katritch V, Han GW, Huang X-P, Vardy E, et al. Structural features for functional selectivity at serotonin receptors. Science. 2013;340:615–9.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Liu W, Wacker D, Gati C, Han GW, James D, Wang D, et al. Serial femtosecond crystallography of G protein-coupled receptors. Science. 2013;342:1521–4.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, et al. Crystal structure of an LSD-bound human serotonin receptor. Cell. 2017;168:377–89.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Hua T, Vemuri K, Nikas SP, Laprairie RB, Wu Y, Qu L, et al. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature. 2017;547:468–71.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Oswald C, Rappas M, Kean J, Doré AS, Errey JC, Bennett K, et al. Intracellular allosteric antagonism of the CCR9 receptor. Nature. 2016;540:462–5.PubMedCrossRefGoogle Scholar
  145. 145.
    Shihoya W, Nishizawa T, Yamashita K, Inoue A, Hirata K, Kadji FMN, et al. X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog. Nat Struct Mol Biol. 2017;24:758–64.PubMedCrossRefGoogle Scholar
  146. 146.
    Burg JS, Ingram JR, Venkatakrishnan AJ, Jude KM, Dukkipati A, Feinberg EN, et al. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor. Science. 2015;347:1113–7.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Zhang D, Gao Z-G, Zhang K, Kiselev E, Crane S, Wang J, et al. Two disparate ligand-binding sites in the human P2Y1 receptor. Nature. 2015;520:317–21.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Zhang J, Zhang K, Gao Z-G, Paoletta S, Zhang D, Han GW, et al. Agonist-bound structure of the human P2Y12 receptor. Nature. 2014;509:119–22.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Zhang K, Zhang J, Gao Z-G, Zhang D, Zhu L, Han GW, et al. Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature. 2014;509:115–8.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Yao Z, Kobilka B. Using synthetic lipids to stabilize purified 𝛽2 adrenoceptor in detergent micelles. Anal Biochem. 2005;343:344–6.PubMedCrossRefGoogle Scholar
  151. 151.
    Pontier SM, Percherancier Y, Galandrin S, Breit A, Galés C, Bouvier M. Cholesterol-dependent separation of the β2-adrenergic receptor from its partners determines signaling efficacy: insight into nanoscale organization of signal transduction. J Biol Chem. 2008;283:24659–72.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Paila YD, Jindal E, Goswami SK, Chattopadhyay A. Cholesterol depletion enhances adrenergic signaling in cardiac myocytes. Biochim Biophys Acta. 2011;1808:461–5.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Zocher M, Zhang C, Rasmussen SGF, Kobilka BK, Müller DJ. Cholesterol increases kinetic, energetic, and mechanical stability of the human β2-adrenergic receptor. Proc Natl Acad Sci U S A. 2012;109:E3463–72.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Lam RS, Nahirney D, Duszyk M. Cholesterol-dependent regulation of adenosine A2A receptor-mediated anion secretion in colon epithelial cells. Exp Cell Res. 2009;315:3028–35.PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Xu W, Yoon S-I, Huang P, Wang Y, Chen C, Chong PL-G, et al. Localization of the κ opioid receptor in lipid rafts. J Pharmacol Exp Ther. 2006;317:1295–306.PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Huang P, Xu W, Yoon S-I, Chen C, Chong PL-G, Liu-Chen LY. Cholesterol reduction by methyl-β-cyclodextrin attenuates the delta opioid receptor-mediated signaling in neuronal cells but enhances it in non-neuronal cells. Biochem Pharmacol. 2007;73:534–49.PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Eroglu C, Brügger B, Wieland F, Sinning I. Glutamate-binding affinity of Drosophila metabotropic glutamate receptor is modulated by association with lipid rafts. Proc Natl Acad Sci U S A. 2003;100:10219–24.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Kumari R, Castillo C, Francesconi A. Agonist-dependent signaling by group I metabotropic glutamate receptors is regulated by association with lipid domains. J Biol Chem. 2013;288:32004–19.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Huang P, Nedelcu D, Watanabe M, Jao C, Kim Y, Liu J, et al. Cellular cholesterol directly activates smoothened in hedgehog signaling. Cell. 2016;166:1176–87.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Porter JA, Young KE, Beachy PA. Cholesterol modification of hedgehog signaling proteins in animal development. Science. 1996;274:255–9.CrossRefGoogle Scholar
  161. 161.
    Turner JH, Gelasco AK, Raymond JR. Calmodulin interacts with the third intracellular loop of the serotonin 5-hydroxytryptamine1A receptor at two distinct sites. Putative role in receptor phosphorylation by protein kinase C. J Biol Chem. 2004;279:17027–37.PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Wheatley M, Wootten D, Conner MT, Simms J, Kendrick R, Logan RT, et al. Lifting the lid on GPCRs: the role of extracellular loops. Br J Pharmacol. 2012;165:1688–703.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Pal S, Aute R, Sarkar P, Bose S, Deshmukh MV, Chattopadhyay A. Constrained dynamics of the sole tryptophan in the third intracellular loop of the serotonin1A receptor. Biophys Chem. 2018;240:34–41.PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Day PW, Rasmussen SGF, Parnot C, Fung JJ, Masood A, Kobilka TS, et al. A monoclonal antibody for G protein-coupled receptor crystallography. Nat Methods. 2007;4:927–9.PubMedCrossRefGoogle Scholar
  165. 165.
    Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS, et al. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science. 2007;318:1266–73.PubMedCrossRefGoogle Scholar
  166. 166.
    Caffrey M. A comprehensive review of the lipid cubic phase or in meso method for crystallizing membrane and soluble proteins and complexes. Acta Crystallogr F Struct Biol Commun. 2015;71:3–18.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Khelashvili G, Albornoz PBC, Johner N, Mondal S, Caffrey M, Weinstein H. Why GPCRs behave differently in cubic and lamellar lipidic mesophases. J Am Chem Soc. 2012;134:15858–68.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Epand RM. Cholesterol and the interaction of proteins with membrane domains. Prog Lipid Res. 2006;45:279–94.PubMedCrossRefGoogle Scholar
  169. 169.
    Li H, Papadopoulos V. Peripheral-type benzodiazepine receptor function in cholesterol transport. Identification of a putative cholesterol recognition/interaction amino acid sequence and consensus pattern. Endocrinology. 1998;139:4991–7.PubMedCrossRefGoogle Scholar
  170. 170.
    Vincent N, Genin C, Malvoisin E. Identification of a conserved domain of the HIV-1 transmembrane protein gp41 which interacts with cholesteryl groups. Biochim Biophys Acta. 2002;1567:157–64.PubMedCrossRefGoogle Scholar
  171. 171.
    Epand RM, Sayer BG, Epand RF. Caveolin scaffolding region and cholesterol-rich domains in membranes. J Mol Biol. 2005;345:339–50.PubMedCrossRefGoogle Scholar
  172. 172.
    Jafurulla M, Tiwari S, Chattopadhyay A. Identification of cholesterol recognition amino acid consensus (CRAC) motif in G-protein coupled receptors. Biochem Biophys Res Commun. 2011;404:569–73.PubMedCrossRefGoogle Scholar
  173. 173.
    Sengupta D, Chattopadhyay A. Identification of cholesterol binding sites in the serotonin1A receptor. J Phys Chem B. 2012;116:12991–6.PubMedCrossRefGoogle Scholar
  174. 174.
    Baier CJ, Fantini J, Barrantes FJ. Disclosure of cholesterol recognition motifs in transmembrane domains of the human nicotinic acetylcholine receptor. Sci Rep. 2011;1:69.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Fantini J, Di Scala C, Evans LS, Williamson PTF, Barrantes FJ. A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes. Sci Rep. 2016;6:21907.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Ballesteros JA, Weinstein H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci. 1995;25:366–428.CrossRefGoogle Scholar
  177. 177.
    Prasanna X, Chattopadhyay A, Sengupta D. Cholesterol modulates the dimer interface of the β 2-adrenergic receptor via cholesterol occupancy sites. Biophys J. 2014;106:1290–300.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Oates J, Faust B, Attrill H, Harding P, Orwick M, Watts A. The role of cholesterol on the activity and stability of neurotensin receptor 1. Biochim Biophys Acta. 2012;1818:2228–33.PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Lee AG. Lipid-protein interactions in biological membranes: a structural perspective. Biochim Biophys Acta. 2003;1612:1–40.PubMedCrossRefPubMedCentralGoogle Scholar
  180. 180.
    Simmonds AC, East JM, Jones OT, Rooney EK, McWhirter J, Lee AG. Annular and non-annular binding sites on the (Ca2+ + Mg2+)-ATPase. Biochim Biophys Acta. 1982;693:398–406.PubMedCrossRefPubMedCentralGoogle Scholar
  181. 181.
    Jones OT, McNamee MG. Annular and nonannular binding sites for cholesterol associated with the nicotinic acetylcholine receptor. Biochemistry. 1988;27:2364–74.PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Marius P, Zagnoni M, Sandison ME, East JM, Morgan H, Lee AG. Binding of anionic lipids to at least three nonannular sites on the potassium channel KcsA is required for channel opening. Biophys J. 2008;94:1689–98.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Guixà-González R, Albasanz JL, Rodriguez-Espigares I, Pastor M, Sanz F, Martí-Solano M, et al. Membrane cholesterol access into a G-protein-coupled receptor. Nat Commun. 2017;8:14505.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    McIntosh TJ. The effect of cholesterol on the structure of phosphatidylcholine bilayers. Biochim Biophys Acta. 1978;513:43–58.PubMedCrossRefGoogle Scholar
  185. 185.
    Simon SA, McIntosh TJ, Latorre R. Influence of cholesterol on water penetration into bilayers. Science. 1982;216:65–7.PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Nezil FA, Bloom M. Combined influence of cholesterol and synthetic amphiphilic peptides upon bilayer thickness in model membranes. Biophys J. 1992;61:1176–83.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    McMullen TPW, Lewis RNAH, McElhaney RN. Differential scanning calorimetric study of the effect of cholesterol on the thermotropic phase behavior of a homologous series of linear saturated phosphatidylcholines. Biochemistry. 1993;32:516–22.PubMedCrossRefPubMedCentralGoogle Scholar
  188. 188.
    Chen Z, Rand RP. The influence of cholesterol on phospholipid membrane curvature and bending elasticity. Biophys J. 1997;73:267–76.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Arora A, Raghuraman H, Chattopadhyay A. Influence of cholesterol and ergosterol on membrane dynamics: a fluorescence approach. Biochem Biophys Res Commun. 2004;318:920–6.PubMedCrossRefPubMedCentralGoogle Scholar
  190. 190.
    Bacia K, Schwille P, Kurzchalia T. Sterol structure determines the separation of phases and the curvature of the liquid-ordered phase in model membranes. Proc Natl Acad Sci U S A. 2005;102:3272–7.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Starke-Peterkovic T, Turner N, Vitha MF, Waller MP, Hibbs DE, Clarke RJ. Cholesterol effect on the dipole potential of lipid membranes. Biophys J. 2006;90:4060–70.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Haldar S, Kanaparthi RK, Samanta A, Chattopadhyay A. Differential effect of cholesterol and its biosynthetic precursors on membrane dipole potential. Biophys J. 2012;102:1561–9.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Yeagle P. The membranes of cells. 3rd ed. Orlando, FL: Academic Press; 2016. p. 200–7.Google Scholar
  194. 194.
    Brejchová J, Sýkora J, Dlouhá K, Roubalová L, Ostašov P, Vošahlíková M, et al. Fluorescence spectroscopy studies of HEK293 cells expressing DOR-Gi1α fusion protein; the effect of cholesterol depletion. Biochim Biophys Acta. 2011;1808:2819–29.PubMedCrossRefPubMedCentralGoogle Scholar
  195. 195.
    Soubias O, Gawrisch K. The role of the lipid matrix for structure and function of the GPCR rhodopsin. Biochim Biophys Acta. 2012;1818:234–40.PubMedCrossRefPubMedCentralGoogle Scholar
  196. 196.
    Pal S, Chakraborty H, Bandari S, Yahioglu G, Suhling K, Chattopadhyay A. Molecular rheology of neuronal membranes explored using a molecular rotor: implications for receptor function. Chem Phys Lipids. 2016;196:69–75.PubMedCrossRefPubMedCentralGoogle Scholar
  197. 197.
    Brown MF. Modulation of rhodopsin function by properties of the membrane bilayer. Chem Phys Lipids. 1994;73:159–80.PubMedCrossRefGoogle Scholar
  198. 198.
    Brown MF. Soft matter in lipid-protein interactions. Annu Rev Biophys. 2017;46:379–410.PubMedCrossRefGoogle Scholar
  199. 199.
    Mitchell DC, Straume M, Miller JL, Litman BJ. Modulation of metarhodopsin formation by cholesterol-induced ordering of bilayer lipids. Biochemistry. 1990;29:9143–9.PubMedCrossRefGoogle Scholar
  200. 200.
    Falck E, Patra M, Karttunen M, Hyvönen MT, Vattulainen I. Impact of cholesterol on voids in phospholipid membranes. J Chem Phys. 2004;121:12676–89.PubMedCrossRefPubMedCentralGoogle Scholar
  201. 201.
    Jafurulla M, Chattopadhyay A. Structural stringency of cholesterol for membrane protein function utilizing stereoisomers as novel tools: a review. Methods Mol Biol. 2017;1583:21–39.PubMedCrossRefPubMedCentralGoogle Scholar
  202. 202.
    Singh P, Haldar S, Chattopadhyay A. Differential effect of sterols on dipole potential in hippocampal membranes: implications for receptor function. Biochim Biophys Acta. 2013;1828:917–23.PubMedCrossRefPubMedCentralGoogle Scholar
  203. 203.
    Clarke RJ. The dipole potential of phospholipid membranes and methods for its detection. Adv Colloid Interface Sci. 2001;89-90:263–81.PubMedCrossRefPubMedCentralGoogle Scholar
  204. 204.
    Duffin RL, Garrett MP, Busath DD. Modulation of lipid bilayer interfacial dipole potential by phloretin, RH421, and 6-ketocholestanol as probed by gramicidin channel conductance. Langmuir. 2003;19:1439–42.CrossRefGoogle Scholar
  205. 205.
    Starke-Peterkovic T, Turner N, Else PL, Clarke RJ. Electric field strength of membrane lipids from vertebrate species: membrane lipid composition and Na+-K+-ATPase molecular activity. Am J Physiol Regul Integr Comp Physiol. 2005;288:R663–70.PubMedCrossRefPubMedCentralGoogle Scholar
  206. 206.
    Bandari S, Chakraborty H, Covey DF, Chattopadhyay A. Membrane dipole potential is sensitive to cholesterol stereospecificity: implications for receptor function. Chem Phys Lipids. 2014;184:25–9.PubMedCrossRefGoogle Scholar
  207. 207.
    Oakes V, Domene C. Stereospecific interactions of cholesterol in a model cell membrane: implications for the membrane dipole potential. J Membr Biol. 2018;251:507–19.PubMedCrossRefPubMedCentralGoogle Scholar
  208. 208.
    Mickus DE, Levitt DG, Rychnovsky SD. Enantiomeric cholesterol as a probe of ion-channel structure. J Am Chem Soc. 1992;114:359–60.CrossRefGoogle Scholar
  209. 209.
    Covey DF. ent-Steroids: novel tools for studies of signaling pathways. Steroids. 2009;74:577–85.PubMedCrossRefPubMedCentralGoogle Scholar
  210. 210.
    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:e19393.PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Kristiana I, Luu W, Stevenson J, Cartland S, Jessup W, Belani JD, et al. Cholesterol through the looking glass: ability of its enantiomer also to elicit homeostatic responses. J Biol Chem. 2012;287:33897–904.PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Westover EJ, Covey DF. The enantiomer of cholesterol. J Membr Biol. 2004;202:61–72.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Md. Jafurulla
    • 1
  • G. Aditya Kumar
    • 1
  • Bhagyashree D. Rao
    • 2
    • 3
  • Amitabha Chattopadhyay
    • 1
    • 3
    Email author
  1. 1.CSIR-Centre for Cellular and Molecular BiologyHyderabadIndia
  2. 2.CSIR-Indian Institute of Chemical TechnologyHyderabadIndia
  3. 3.Academy of Scientific and Innovative ResearchGhaziabadIndia

Personalised recommendations

Cite chapter

Buy options