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Annual Review of Pharmacology and Toxicology

Volume 60, 2020

Lipid-Dependent Regulation of Ion Channels and G Protein–Coupled Receptors: Insights from Structures and Simulations

Abstract

Ion channels and G protein–coupled receptors (GPCRs) are regulated by lipids in their membrane environment. Structural studies combined with biophysical and molecular simulation investigations reveal interaction sites for specific lipids on membrane protein structures. For K channels, PIP plays a key role in regulating Kv and Kir channels. Likewise, several recent cryo-EM structures of TRP channels have revealed bound lipids, including PIP and cholesterol. Among the pentameric ligand-gated ion channel family, structural and biophysical studies suggest the M4 TM helix may act as a lipid sensor, e.g., forming part of the binding sites for neurosteroids on the GABA receptor. Structures of GPCRs have revealed multiple cholesterol sites, which may modulate both receptor dynamics and receptor oligomerization. PIP also interacts with GPCRs and may modulate their interactions with G proteins. Overall, it is evident that multiple lipid binding sites exist on channels and receptors that modulate their function allosterically and are potential druggable sites.

Keyword(s): cholesterol, GPCR, molecular dynamics, PIP2, pLGIC, potassium channel, TRP channel
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/content/journals/10.1146/annurev-pharmtox-010919-023411
2020-01-06
2024-04-19
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Literature Cited

  1. 1. 
    Cheng YF. 2018. Membrane protein structural biology in the era of single particle cryo-EM. Curr. Opin. Struct. Biol. 52:58–63
     [Google Scholar]
  2. 2. 
    Hedger G, Sansom MSP. 2016. Lipid interaction sites on channels, transporters and receptors: recent insights from molecular dynamics simulations. Biochim. Biophys. Acta 1858:2390–400
     [Google Scholar]
  3. 3. 
    Suh BC, Hille B. 2008. PIP2 is a necessary cofactor for ion channel function: how and why?. Annu. Rev. Biophys. 37:175–95
     [Google Scholar]
  4. 4. 
    Hansen SB. 2015. Lipid agonism: the PIP2 paradigm of ligand-gated ion channels. Biochim. Biophys. Acta 1851:620–28
     [Google Scholar]
  5. 5. 
    Levitan I, Singh DK, Rosenhouse-Dantsker A 2014. Cholesterol binding to ion channels. Front. Physiol. 5:65
     [Google Scholar]
  6. 6. 
    Valiyaveetil FI, Zhou Y, MacKinnon R 2002. Lipids in the structure, folding and function of the KcsA K+ channel. Biochemisty 41:10771–77
     [Google Scholar]
  7. 7. 
    Alvis SJ, Williamson IM, East JM, Lee AG 2003. Interactions of anionic phospholipids and phosphatidylethanolamine with the potassium channel KcsA. Biophys. J. 85:3828–38
     [Google Scholar]
  8. 8. 
    Deol SS, Domene C, Bond PJ, Sansom MSP 2006. Anionic phospholipid interactions with the potassium channel KcsA: simulation studies. Biophys. J. 90:822–30
     [Google Scholar]
  9. 9. 
    Long SB, Tao X, Campbell EB, MacKinnon R 2007. Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature 450:376–82
     [Google Scholar]
  10. 10. 
    Ramu Y, Xu YP, Lu Z 2006. Enzymatic activation of voltage-gated potassium channels. Nature 442:696–99
     [Google Scholar]
  11. 11. 
    Schmidt D, Jiang QX, MacKinnon R 2006. Phospholipids and the origin of cationic gating charges in voltage sensors. Nature 444:775–79
     [Google Scholar]
  12. 12. 
    Xu YP, Ramu Y, Lu Z 2008. Removal of phospho-head groups of membrane lipids immobilizes voltage sensors of K+ channels. Nature 451:826–29
     [Google Scholar]
  13. 13. 
    Zheng H, Liu WR, Anderson LY, Jiang QX 2011. Lipid-dependent gating of a voltage-gated potassium channel. Nat. Commun. 2:250
     [Google Scholar]
  14. 14. 
    Sands ZA, Sansom MSP. 2007. How does a voltage sensor interact with a lipid bilayer? Simulations of a potassium channel domain. Structure 15:235–44
     [Google Scholar]
  15. 15. 
    Kruse M, Hammond GRV, Hille B 2012. Regulation of voltage-gated potassium channels by PI(4,5)P2. J. Gen. Physiol. 140:189–205
     [Google Scholar]
  16. 16. 
    Rodriguez-Menchaca AA, Adney SK, Tang QY, Meng XY, Rosenhouse-Dantsker A et al. 2012. PIP2 controls voltage-sensor movement and pore opening of Kv channels through the S4-S5 linker. PNAS 109:E2399–408
     [Google Scholar]
  17. 17. 
    Loussouarn G, Park KH, Bellocq C, Baro I, Charpentier F, Escande D 2003. Phosphatidylinositol-4,5-bisphosphate, PIP2, controls KCNQ1/KCNE1 voltage-gated potassium channels: a functional homology between voltage-gated and inward rectifier K+ channels. EMBO J 22:5412–21
     [Google Scholar]
  18. 18. 
    Zhou PZ, Yu HB, Gu M, Nan FJ, Gao ZB, Li M 2013. Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels. PNAS 110:8726–31
     [Google Scholar]
  19. 19. 
    Zaydman MA, Silva JR, Delaloye K, Li Y, Liang HW et al. 2013. Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening. PNAS 110:13180–85
     [Google Scholar]
  20. 20. 
    Zhang QS, Zhou PZ, Chen ZX, Li M, Jiang HL et al. 2013. Dynamic PIP2 interactions with voltage sensor elements contribute to KCNQ2 channel gating. PNAS 110:20093–98
     [Google Scholar]
  21. 21. 
    Eckey K, Wrobel E, Strutz-Seebohm N, Pott L, Schmitt N, Seebohm G 2014. Novel Kv7.1-phosphatidylinositol 4,5-bisphosphate interaction sites uncovered by charge neutralization scanning. J. Biol. Chem. 289:22749–58
     [Google Scholar]
  22. 22. 
    Kim RY, Pless SA, Kurata HT 2017. PIP2 mediates functional coupling and pharmacology of neuronal KCNQ channels. PNAS 114:E9702–11
     [Google Scholar]
  23. 23. 
    Kasimova MA, Zaydman MA, Cui JM, Tarek M 2015. PIP2-dependent coupling is prominent in Kv7.1 due to weakened interactions between S4-S5 and S6. Sci. Rep. 5:7474
     [Google Scholar]
  24. 24. 
    Kasimova MA, Tarek M, Shaytan AK, Shaitan KV, Delemotte L 2014. Voltage-gated ion channel modulation by lipids: insights from molecular dynamics simulations. Biochim. Biophys. Acta Biomembr. 1838:1322–31
     [Google Scholar]
  25. 25. 
    Chen L, Zhang Q, Qiu Y, Li Z, Chen Z et al. 2015. Migration of PIP2 lipids on voltage-gated potassium channel surface influences channel deactivation. Sci. Rep. 5:15079
     [Google Scholar]
  26. 26. 
    Choveau FS, De la Rosa V, Bierbower SM, Hernandez CC, Shapiro MS 2018. Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates KCNQ3 K+ channels by interacting with four cytoplasmic channel domains. J. Biol. Chem. 293:19411–28
     [Google Scholar]
  27. 27. 
    Taylor KC, Sanders CR. 2017. Regulation of KCNQ/Kv7 family voltage-gated K+ channels by lipids. Biochim. Biophys. Acta 1859:586–97
     [Google Scholar]
  28. 28. 
    Yazdi S, Stein M, Elinder F, Andersson M, Lindahl E 2016. The molecular basis of polyunsaturated fatty acid interactions with the Shaker voltage-gated potassium channel. PLOS Comp. Biol. 12:e1004704
     [Google Scholar]
  29. 29. 
    Pottosin, II, Valencia-Cruz G, Bonales-Alatorre E, Shabala SN, Dobrovinskaya OR 2007. Methyl-β-cyclodextrin reversibly alters the gating of lipid rafts-associated Kv1.3 channels in Jurkat T lymphocytes. Pflugers Arch 454:235–44
     [Google Scholar]
  30. 30. 
    Whicher JR, MacKinnon R. 2016. Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science 353:664–69
     [Google Scholar]
  31. 31. 
    Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A et al. 2005. International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacol. Rev. 57:509–26
     [Google Scholar]
  32. 32. 
    Ryan DP, da Silva MRD, Soong TW, Fontaine B, Donaldson MR et al. 2010. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell 140:88–98
     [Google Scholar]
  33. 33. 
    Huang CL, Feng SY, Hilgemann DW 1998. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gβγ. Nature 391:803–6
     [Google Scholar]
  34. 34. 
    Rohacs T, Chen J, Prestwich GD, Logothetis DE 1999. Distinct specificities of inwardly rectifying K+ channels for phosphoinositides. J. Biol. Chem. 274:36065–72
     [Google Scholar]
  35. 35. 
    Rohacs T, Lopes CMB, Jin TH, Ramdya PP, Molnar Z, Logothetis DE 2003. Specificity of activation by phosphoinositides determines lipid regulation of Kir channels. PNAS 100:745–50
     [Google Scholar]
  36. 36. 
    Fürst O, Mondou B, D'Avanzo N 2014. Phosphoinositide regulation of inward rectifier potassium (Kir) channels. Front. Physiol. 4:404
     [Google Scholar]
  37. 37. 
    Enkvetchakul D, Loussouarn G, Makhina E, Shyng SL, Nichols CG 2000. The kinetic and physical basis of KATP channel gating: toward a unified molecular understanding. Biophys. J. 78:2334–48
     [Google Scholar]
  38. 38. 
    Hansen SB, Tao X, MacKinnon R 2011. Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2. Nature 477:495–98
     [Google Scholar]
  39. 39. 
    Lee SJ, Ren FF, Zangerl-Plessl EM, Heyman S, Stary-Weinzinger A et al. 2016. Structural basis of control of inward rectifier Kir2 channel gating by bulk anionic phospholipids. J. Gen. Physiol. 148:227–37
     [Google Scholar]
  40. 40. 
    Whorton MR, MacKinnon R. 2011. Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium. Cell 147:199–208
     [Google Scholar]
  41. 41. 
    Whorton MR, MacKinnon R. 2013. X-ray structure of the mammalian GIRK2-βγ G-protein complex. Nature 498:190–97
     [Google Scholar]
  42. 42. 
    Li NN, Wu JX, Ding D, Cheng JX, Gao N, Chen L 2017. Structure of a pancreatic ATP-sensitive potassium channel. Cell 168:101–10
     [Google Scholar]
  43. 43. 
    Stansfeld PJ, Hopkinson R, Ashcroft FM, Sansom MSP 2009. PIP2-binding site in Kir channels: definition by multiscale biomolecular simulations. Biochemisty 48:10926–33
     [Google Scholar]
  44. 44. 
    Schmidt MR, Stansfeld PJ, Tucker SJ, Sansom MSP 2013. Simulation-based prediction of phosphatidylinositol 4,5-bisphosphate binding to an ion channel. Biochemisty 52:279–81
     [Google Scholar]
  45. 45. 
    Lacin E, Aryal P, Glaaser I, Bodhinathan K, Tsai E et al. 2017. Dynamic role of the tether helix in PIP2-dependent gating of a neuronal GIRK potassium channel. J. Gen. Physiol. 149:799–811
     [Google Scholar]
  46. 46. 
    Cheng WWL, D'Avanzo N, Doyle DA, Nichols CG 2011. Dual-mode phospholipid regulation of human inward rectifying potassium channels. Biophys. J. 100:620–28
     [Google Scholar]
  47. 47. 
    Lee S-J, Wang S, Borschel W, Heyman S, Gyore J, Nichols CG 2013. Secondary anionic phospholipid binding site and gating mechanism in Kir2.1 inward rectifier channels. Nat. Commun. 4:2786
     [Google Scholar]
  48. 48. 
    Romanenko VG, Fang Y, Byfield F, Travis AJ, Vandenberg CA et al. 2004. Cholesterol sensitivity and lipid raft targeting of Kir2.1 channels. Biophys. J. 87:3850–61
     [Google Scholar]
  49. 49. 
    Hibino H, Kurachi Y. 2007. Distinct detergent-resistant membrane microdomains (lipid rafts) respectively harvest K+ and water transport systems in brain astroglia. Eur. J. Neurosci. 26:2539–55
     [Google Scholar]
  50. 50. 
    D'Avanzo N, Hyrc K, Enkvetchakul D, Covey DF, Nichols CG 2011. Enantioselective protein-sterol interactions mediate regulation of both prokaryotic and eukaryotic inward rectifier K+ channels by cholesterol. PLOS ONE 6:e19393
     [Google Scholar]
  51. 51. 
    Epshtein Y, Chopra AP, Rosenhouse-Dantsker A, Kowalsky GB, Logothetis DE, Levitan I 2009. Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol. PNAS 106:8055–60
     [Google Scholar]
  52. 52. 
    Rosenhouse-Dantsker A, Noskov S, Han HZ, Adney SK, Tang QY et al. 2012. 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)P2). J. Biol. Chem. 287:40266–78
     [Google Scholar]
  53. 53. 
    Rosenhouse-Dantsker A, Noskov S, Logothetis DE, Levitan I 2013. Cholesterol sensitivity of KIR2.1 depends on functional inter-links between the N and C termini. Channels 7:303–12
     [Google Scholar]
  54. 54. 
    Rosenhouse-Dantsker A, Noskov S, Durdagi S, Logothetis DE, Levitan I 2013. Identification of novel cholesterol-binding regions in Kir2 channels. J. Biol. Chem. 288:31154–64
     [Google Scholar]
  55. 55. 
    Fürst O, Nichols CG, Lamoureux G, D'Avanzo N 2014. Identification of a cholesterol-binding pocket in inward rectifier K+ (Kir) channels. Biophys. J. 107:2786–96
     [Google Scholar]
  56. 56. 
    Barbera N, Ayee MAA, Akpa BS, Levitan I 2018. Molecular dynamics simulations of Kir2.2 interactions with an ensemble of cholesterol molecules. Biophys. J. 115:1264–80
     [Google Scholar]
  57. 57. 
    McClenaghan C, Schewe M, Aryal P, Carpenter EP, Baukrowitz T, Tucker SJ 2016. Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states. J. Gen. Physiol. 147:497–505
     [Google Scholar]
  58. 58. 
    Brohawn SG, Campbell EB, MacKinnon R 2014. Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel. Nature 516:126–30
     [Google Scholar]
  59. 59. 
    Brohawn SG, Su ZW, MacKinnon R 2014. Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels. PNAS 111:3614–19
     [Google Scholar]
  60. 60. 
    Aryal P, Jarerattanachat V, Clausen MV, Schewe M, McClenaghan C et al. 2017. Bilayer-mediated structural transitions control mechanosensitivity of the TREK-2 K2P channel. Structure 25:708–18
     [Google Scholar]
  61. 61. 
    Clausen MV, Jarerattanachat V, Carpenter EP, Sansom MSP, Tucker SJ 2017. Asymmetric mechanosensitivity in a eukaryotic ion channel. PNAS 114:E8343–51
     [Google Scholar]
  62. 62. 
    Dong YY, Pike ACW, Mackenzie A, McClenaghan C, Aryal P et al. 2015. K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac. Science 347:1256–59
     [Google Scholar]
  63. 63. 
    Brennecke JT, de Groot BL 2018. Mechanism of mechanosensitive gating of the TREK-2 potassium channel. Biophys. J. 114:1336–43
     [Google Scholar]
  64. 64. 
    Venkatachalam K, Montell C. 2007. TRP channels. Annu. Rev. Biochem. 76:387–417
     [Google Scholar]
  65. 65. 
    Nilius B, Owsianik G. 2010. Transient receptor potential channelopathies. Pflugers Arch 460:437–50
     [Google Scholar]
  66. 66. 
    Moran MM. 2018. TRP channels as potential drug targets. Annu. Rev. Pharmacol. Toxicol. 58:309–29
     [Google Scholar]
  67. 67. 
    Madej MG, Ziegler CM. 2018. Dawning of a new era in TRP channel structural biology by cryo-electron microscopy. Pflugers Arch 470:213–25
     [Google Scholar]
  68. 68. 
    Ciardo MG, Ferrer-Montiel A. 2017. Lipids as central modulators of sensory TRP channels. Biochim. Biophys. Acta Biomembr. 1859:1615–28
     [Google Scholar]
  69. 69. 
    Palazzo E, Rossi F, de Novellis V, Maione S 2013. Endogenous modulators of TRP channels. Curr. Top. Med. Chem. 13:398–407
     [Google Scholar]
  70. 70. 
    Brauchi S, Orta G, Mascayano C, Salazar M, Raddatz N et al. 2007. Dissection of the components for PIP2 activation and thermosensation in TRP channels. PNAS 104:10246–51
     [Google Scholar]
  71. 71. 
    Rohacs T. 2007. Regulation of TRP channels by PIP2. Pflugers Arch 453:753–62
     [Google Scholar]
  72. 72. 
    Rohacs T. 2009. Phosphoinositide regulation of non-canonical transient receptor potential channels. Cell Calcium 45:554–65
     [Google Scholar]
  73. 73. 
    Steinberg X, Lespay-Rebolledo C, Brauchi S 2014. A structural view of ligand-dependent activation in thermoTRP channels. Front. Physiol. 5:171
     [Google Scholar]
  74. 74. 
    Klein RM, Ufret-Vincenty CA, Hua L, Gordon SE 2008. Determinants of molecular specificity in phosphoinositide regulation. J. Biol. Chem. 283:26208–16
     [Google Scholar]
  75. 75. 
    Lee J, Cha SK, Sun TJ, Huang CL 2005. PIP2 activates TRPV5 and releases its inhibition by intracellular Mg2+. J. Gen. Physiol. 126:439–51
     [Google Scholar]
  76. 76. 
    Thyagarajan B, Lukacs V, Rohacs T 2008. Hydrolysis of phosphatidylinositol 4,5-bisphosphate mediates calcium-induced inactivation of TRPV6 channels. J. Biol. Chem. 283:14980–87
     [Google Scholar]
  77. 77. 
    Toth BI, Konrad M, Ghosh D, Mohr F, Halaszovich CR et al. 2015. Regulation of the transient receptor potential channel TRPM3 by phosphoinositides. J. Gen. Physiol. 146:51–63
     [Google Scholar]
  78. 78. 
    Zhang Z, Okawa H, Wang YY, Liman ER 2005. Phosphatidylinositol 4,5-bisphosphate rescues TRPM4 channels from desensitization. J. Biol. Chem. 280:39185–92
     [Google Scholar]
  79. 79. 
    Liu D, Liman ER. 2003. Intracellular Ca2+ and the phospholipid PIP2 regulate the taste transduction ion channel TRPM5. PNAS 100:15160–65
     [Google Scholar]
  80. 80. 
    Runnels LW, Yue LX, Clapham DE 2002. The TRPM7 channel is inactivated by PIP2 hydrolysis. Nat. Cell Biol. 4:329–36
     [Google Scholar]
  81. 81. 
    Daniels RL, Takashima Y, McKemy DD 2009. Activity of the neuronal cold sensor TRPM8 is regulated by phospholipase C via the phospholipid phosphoinositol 4,5-bisphosphate. J. Biol. Chem. 284:1570–82
     [Google Scholar]
  82. 82. 
    Gao Y, Cao EH, Julius D, Cheng YF 2016. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature 534:347–51
     [Google Scholar]
  83. 83. 
    Zubcevic L, Herzik MA, Chung BC, Liu ZR, Lander GC, Lee SY 2016. Cryo-electron microscopy structure of the TRPV2 ion channel. Nat. Struct. Mol. Biol. 23:180–86
     [Google Scholar]
  84. 84. 
    Hughes TET, Pumroy RA, Yazick AT, Kasimova MA, Fluck EC et al. 2018. Structural insights on TRPV5 gating by endogenous modulators. Nat. Commun. 9:4198
     [Google Scholar]
  85. 85. 
    Chen QF, She J, Zeng WZ, Guo JT, Xu HX et al. 2017. Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. Nature 550:415–18
     [Google Scholar]
  86. 86. 
    Fan C, Choi W, Sun WN, Du J, Lu W 2018. Structure of the human lipid-gated cation channel TRPC3. eLife 7:e36852
     [Google Scholar]
  87. 87. 
    Tang QL, Guo WJ, Zheng L, Wu JX, Liu M et al. 2018. Structure of the receptor-activated human TRPC6 and TRPC3 ion channels. Cell Res 28:746–55
     [Google Scholar]
  88. 88. 
    Yin Y, Le SC, Hsu AL, Borgnia MJ, Yang H, Lee S-Y 2019. Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel. Science 363: 6430):eaav9334
    [Google Scholar]
  89. 89. 
    Wang Q, Hedger G, Aryal P, Grieben M, Nazrallah C et al. 2019. Lipid interactions of a ciliary membrane TRP channel: simulation and structural studies of polycystin-2 (PC2). bioRxiv 589515. https://doi.org/10.1101/589515
    [Crossref]
  90. 90. 
    Morales-Lazaro SL, Rosenbaum T. 2017. Multiple mechanisms of regulation of transient receptor potential ion channels by cholesterol. Curr. Top. Membr. 80:139–61
     [Google Scholar]
  91. 91. 
    Duan JJ, Li ZL, Li J, Santa-Cruz A, Sanchez-Martinez S et al. 2018. Structure of full-length human TRPM4. PNAS 115:2377–82
     [Google Scholar]
  92. 92. 
    Autzen HE, Myasnikov AG, Campbell MG, Asarnow D, Julius D, Cheng YF 2018. Structure of the human TRPM4 ion channel in a lipid nanodisc. Science 359:228–32
     [Google Scholar]
  93. 93. 
    Vinayagam D, Mager T, Apelbaum A, Bothe A, Merino F et al. 2018. Electron cryo-microscopy structure of the canonical TRPC4 ion channel. eLife 7:e36615
     [Google Scholar]
  94. 94. 
    Lee AG. 2018. A database of predicted binding sites for cholesterol on membrane proteins, deep in the membrane. Biophys. J. 115:522–32
     [Google Scholar]
  95. 95. 
    Bocquet N, Nury H, Baaden M, Le Poupon C, Changeux JP et al. 2009. X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 457:111–14
     [Google Scholar]
  96. 96. 
    Hilf RJC, Dutzler R. 2009. Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 457:115–118
     [Google Scholar]
  97. 97. 
    Hilf RJC, Dutzler R. 2008. X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452:375–79
     [Google Scholar]
  98. 98. 
    Dacosta CJB, Baenziger JE. 2013. Gating of pentameric ligand-gated ion channels: structural insights and ambiguities. Structure 21:1271–83
     [Google Scholar]
  99. 99. 
    Baenziger JE, Corringer PJ. 2011. 3D structure and allosteric modulation of the transmembrane domain of pentameric ligand-gated ion channels. Neuropharmacology 60:116–25
     [Google Scholar]
  100. 100. 
    Borroni MV, Valles AS, Barrantes FJ 2016. The lipid habitats of neurotransmitter receptors in brain. Biochim. Biophys. Acta 1858:2662–70
     [Google Scholar]
  101. 101. 
    Baenziger JE, Henault CM, Therien JPD, Sun J 2015. Nicotinic acetylcholine receptor-lipid interactions: mechanistic insight and biological function. Biochim. Biophys. Acta 1848:1806–17
     [Google Scholar]
  102. 102. 
    Basak S, Schmandt N, Gicheru Y, Chakrapani S 2017. Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel. eLife 6:e23886
     [Google Scholar]
  103. 103. 
    Sauguet L, Poitevin F, Murail S, Van Renterghem C, Moraga-Cid G et al. 2013. Structural basis for ion permeation mechanism in pentameric ligand-gated ion channels. EMBO J 32:728–41
     [Google Scholar]
  104. 104. 
    Nury H, Van Renterghem C, Weng Y, Tran A, Baaden M et al. 2011. X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature 469:428–31
     [Google Scholar]
  105. 105. 
    Althoff T, Hibbs RE, Banerjee S, Gouaux E 2014. X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. Nature 512:333–37
     [Google Scholar]
  106. 106. 
    Yoluk O, Bromstrup T, Bertaccini EJ, Trudell JR, Lindahl E 2013. Stabilization of the GluCl ligand-gated ion channel in the presence and absence of ivermectin. Biophys. J. 105:640–47
     [Google Scholar]
  107. 107. 
    Laverty D, Desai R, Uchański T, Masiulis S, Stec WJ et al. 2019. Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer. Nature 565:516–20
     [Google Scholar]
  108. 108. 
    Walsh RM, Roh SH, Gharpure A, Morales-Perez CL, Teng JF, Hibbs RE 2018. Structural principles of distinct assemblies of the human α4β2 nicotinic receptor. Nature 557:261–65
     [Google Scholar]
  109. 109. 
    Miller PS, Scott S, Masiulis S, De Colibus L, Pardon E et al. 2017. Structural basis for GABAA receptor potentiation by neurosteroids. Nat. Struct. Mol. Biol. 24:986–92
     [Google Scholar]
  110. 110. 
    Laverty D, Thomas P, Field M, Andersen OJ, Gold MG et al. 2017. Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites. Nat. Struct. Mol. Biol. 24:977–85
     [Google Scholar]
  111. 111. 
    Chen Q, Wells MM, Arjunan P, Tillman TS, Cohen AE et al. 2018. Structural basis of neurosteroid anesthetic action on GABAA receptors. Nat. Commun. 9:3972
     [Google Scholar]
  112. 112. 
    Glukhova A, Draper-Joyce CJ, Sunahara RK, Christopoulos A, Wootten D, Sexton PM 2018. Rules of engagement: GPCRs and G proteins. ACS Pharmacol. Transl. Sci. 1:73–83
     [Google Scholar]
  113. 113. 
    Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE 2017. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Disc. 16:829–42
     [Google Scholar]
  114. 114. 
    Fredriksson R, Lagerström MC, Lundin L-G, Schiöth HB 2003. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 63:1256–72
     [Google Scholar]
  115. 115. 
    Mitchell DC, Niu S-L, Litman BJ 2001. Optimization of receptor–G protein coupling by bilayer lipid composition I: kinetics of rhodopsin-transducin binding. J. Biol. Chem. 276:42801–6
     [Google Scholar]
  116. 116. 
    Botelho AV, Huber T, Sakmar TP, Brown MF 2006. Curvature and hydrophobic forces drive oligomerization and modulate activity of rhodopsin in membranes. Biophys. J. 91:4464–77
     [Google Scholar]
  117. 117. 
    Botelho AV, Gibson NJ, Thurmond RL, Wang Y, Brown MF 2002. Conformational energetics of rhodopsin modulated by nonlamellar-forming lipids. Biochemistry 41:6354–68
     [Google Scholar]
  118. 118. 
    Soubias O, Gawrisch K. 2005. Probing specific lipid-protein interaction by saturation transfer difference NMR spectroscopy. J. Am. Chem. Soc. 127:13110–11
     [Google Scholar]
  119. 119. 
    Soubias O, Teague WE, Hines KG, Mitchell DC, Gawrisch K 2010. Contribution of membrane elastic energy to rhodopsin function. Biophys. J. 99:817–24
     [Google Scholar]
  120. 120. 
    Salas-Estrada LA, Leioatts N, Romo TD, Grossfield A 2018. Lipids alter rhodopsin function via ligand-like and solvent-like interactions. Biophys. J. 114:355–67
     [Google Scholar]
  121. 121. 
    Jazayeri A, Dore AS, Lamb D, Krishnamurthy H, Southall SM et al. 2016. Extra-helical binding site of a glucagon receptor antagonist. Nature 533:274–77
     [Google Scholar]
  122. 122. 
    Song G, Yang D, Wang Y, de Graaf C, Zhou Q et al. 2017. Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature 546:312–15
     [Google Scholar]
  123. 123. 
    Zhang Y, Sun B, Feng D, Hu H, Chu M et al. 2017. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546:248–53
     [Google Scholar]
  124. 124. 
    Lu J, Byrne N, Wang J, Bricogne G, Brown FK et al. 2017. Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat. Struct. Mol. Biol. 24:570
     [Google Scholar]
  125. 125. 
    Katritch V, Cherezov V, Stevens RC 2013. Structure-function of the G protein-coupled receptor superfamily. Annu. Rev. Pharmacol. Toxicol. 53:531–56
     [Google Scholar]
  126. 126. 
    Ye L, Van Eps N, Zimmer M, Ernst OP, Prosser RS 2016. Activation of the A2A adenosine G-protein-coupled receptor by conformational selection. Nature 533:265–68
     [Google Scholar]
  127. 127. 
    Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola V-P et al. 2008. A specific cholesterol binding site is established by the 2.8 Å structure of the human β2-adrenergic receptor. Structure 16:897–905
     [Google Scholar]
  128. 128. 
    Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF, Thian FS et al. 2007. High-resolution crystal structure of an engineered human β2-adrenergic G protein–coupled receptor. Science 318:1258–65
     [Google Scholar]
  129. 129. 
    Wacker D, Fenalti G, Brown MA, Katritch V, Abagyan R et al. 2010. Conserved binding mode of human β2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography. J. Am. Chem. Soc. 132:11443–45
     [Google Scholar]
  130. 130. 
    Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D et al. 2011. Structure and function of an irreversible agonist-β2 adrenoceptor complex. Nature 469:236–40
     [Google Scholar]
  131. 131. 
    Liu XY, Ahn S, Kahsai AW, Meng KC, Latorraca NR et al. 2017. Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure. Nature 548:480–84
     [Google Scholar]
  132. 132. 
    Zhang J, Zhang KH, Gao ZG, Paoletta S, Zhang DD et al. 2014. Agonist-bound structure of the human P2Y12 receptor. Nature 509:119–22
     [Google Scholar]
  133. 133. 
    Wacker D, Wang C, Katritch V, Han GW, Huang XP et al. 2013. Structural features for functional selectivity at serotonin receptors. Science 340:615–19
     [Google Scholar]
  134. 134. 
    Liu W, Wacker D, Gati C, Han GW, James D et al. 2013. Serial femtosecond crystallography of G protein–coupled receptors. Science 342:1521–24
     [Google Scholar]
  135. 135. 
    Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ et al. 2017. Crystal structure of an LSD-bound human serotonin receptor. Cell 168:377–89
     [Google Scholar]
  136. 136. 
    McCorvy JD, Wacker D, Wang S, Agegnehu B, Liu J et al. 2018. Structural determinants of 5-HT2B receptor activation and biased agonism. Nat. Struct. Mol. Biol. 25:787–96
     [Google Scholar]
  137. 137. 
    Zhang D, Gao ZG, Zhang K, Kiselev E, Crane S et al. 2015. Two disparate ligand-binding sites in the human P2Y1 receptor. Nature 520:317–21
     [Google Scholar]
  138. 138. 
    Cang X, Yang L, Yang J, Luo C, Zheng M et al. 2014. Cholesterol-β1AR interaction versus cholesterol-β2AR interaction. Proteins 82:760–70
     [Google Scholar]
  139. 139. 
    Manna M, Niemelä M, Tynkkynen J, Javanainen M, Kulig W et al. 2016. Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol. eLife 5:e18432
     [Google Scholar]
  140. 140. 
    Casiraghi M, Damian M, Lescop E, Point E, Moncoq K et al. 2016. Functional modulation of a G protein-coupled receptor conformational landscape in a lipid bilayer. J. Am. Chem. Soc. 138:11170–75
     [Google Scholar]
  141. 141. 
    Prasanna X, Sengupta D, Chattopadhyay A 2016. Cholesterol-dependent conformational plasticity in GPCR dimers. Sci. Rep. 6:31858
     [Google Scholar]
  142. 142. 
    Pluhackova K, Gahbauer S, Kranz F, Wassenaar TA, Bockmann RA 2016. Dynamic cholesterol-conditioned dimerization of the G protein coupled chemokine receptor type 4. PLOS Comp. Biol. 12:e1005169
     [Google Scholar]
  143. 143. 
    Stenkamp RE. 2008. Alternative models for two crystal structures of bovine rhodopsin. Acta Crystallogr. D Biol. Crystallogr. 64: Pt. 8 902–4
     [Google Scholar]
  144. 144. 
    Murakami M, Kouyama T. 2008. Crystal structure of squid rhodopsin. Nature 453:363
     [Google Scholar]
  145. 145. 
    Dawaliby R, Trubbia C, Delporte C, Masureel M, Van Antwerpen P et al. 2016. Allosteric regulation of G protein-coupled receptor activity by phospholipids. Nat. Chem. Biol. 12:35–39
     [Google Scholar]
  146. 146. 
    Neale C, Herce HD, Pomès R, García AE 2015. Can specific protein-lipid interactions stabilize an active state of the beta 2 adrenergic receptor?. Biophys. J. 109:1652–62
     [Google Scholar]
  147. 147. 
    Komolov KE, Du Y, Duc NM, Betz RM, Rodrigues J et al. 2017. Structural and functional analysis of a b2-adrenergic receptor complex with GRK5. Cell 169:407–21
     [Google Scholar]
  148. 148. 
    Yen HY, Hoi KK, Liko I, Hedger G, Horrell MR et al. 2018. PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling. Nature 559:424–27
     [Google Scholar]
  149. 149. 
    Song W, Yen H-Y, Robinson CV, Sansom MSP 2019. State-dependent lipid interactions with the A2a receptor revealed by MD simulations using in vivo-mimetic membranes. Structure 27:392–403
     [Google Scholar]
  150. 150. 
    Pandy-Szekeres G, Munk C, Tsonkov TM, Mordalski S, Harpsoe K et al. 2018. GPCRdb in 2018: adding GPCR structure models and ligands. Nucl. Acids Res. 46:D440–46
     [Google Scholar]
  151. 151. 
    Wu H, Wang C, Gregory KJ, Han GW, Cho HP et al. 2014. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 344:58–64
     [Google Scholar]
  152. 152. 
    Koehl A, Hu H, Feng D, Sun B, Zhang Y et al. 2019. Structural insights into the activation of metabotropic glutamate receptors. Nature 566:79–84
     [Google Scholar]
  153. 153. 
    Zhang XJ, Dong SW, Xu F 2018. Structural and druggability landscape of frizzled G protein-coupled receptors. Trends Biochem. Sci. 43:1033–46
     [Google Scholar]
  154. 154. 
    Eaton S. 2008. Multiple roles for lipids in the Hedgehog signalling pathway. Nat. Rev. Mol. Cell Biol. 9:437–45
     [Google Scholar]
  155. 155. 
    Myers BR, Neahring L, Zhang Y, Roberts KJ, Beachy PA 2017. Rapid, direct activity assays for Smoothened reveal Hedgehog pathway regulation by membrane cholesterol and extracellular sodium. PNAS 114:E11141–50
     [Google Scholar]
  156. 156. 
    Byrne EFX, Sircar R, Miller PS, Hedger G, Luchetti G et al. 2016. Structural basis of Smoothened regulation by its extracellular domains. Nature 535:517–22
     [Google Scholar]
  157. 157. 
    Huang P, Nedelcu D, Watanabe M, Jao C, Kim Y et al. 2016. Cellular cholesterol directly activates Smoothened in Hedgehog signaling. Cell 166:1176–87
     [Google Scholar]
  158. 158. 
    Byrne EFX, Luchetti G, Rohatgi R, Siebold C 2018. Multiple ligand binding sites regulate the Hedgehog signal transducer Smoothened in vertebrates. Curr. Opin. Cell Biol. 51:81–88
     [Google Scholar]
  159. 159. 
    Hedger G, Koldsø H, Chavent M, Siebold C, Rohatgi R, Sansom MSP 2019. Cholesterol interaction sites on the transmembrane domain of the hedgehog signal transducer and Class F G protein-coupled receptor Smoothened. Structure 27:549–59
     [Google Scholar]
  160. 160. 
    Huang P, Zheng S, Wierbowski BM, Kim Y, Nedelcu D et al. 2018. Structural basis of Smoothened activation in Hedgehog signaling. Cell 174:312–24
     [Google Scholar]
  161. 161. 
    van Meer G, Voelker DR, Feigenson GW 2008. Membrane lipids: where they are and how they behave. Nat. Rev. Mol. Cell Biol. 9:112–24
     [Google Scholar]
  162. 162. 
    Dupuy AD, Engelman DM. 2008. Protein area occupancy at the center of the red blood cell membrane. PNAS 105:2848–52
     [Google Scholar]
  163. 163. 
    Lingwood D, Simons K. 2010. Lipid rafts as a membrane-organizing principle. Science 327:46–50
     [Google Scholar]
  164. 164. 
    van den Bogaart G, Meyenberg K, Risselada HJ, Amin H, Willig KI et al. 2011. Membrane protein sequestering by ionic protein-lipid interactions. Nature 479:552–55
     [Google Scholar]
  165. 165. 
    Dart C. 2010. Lipid microdomains and the regulation of ion channel function. J. Physiol. 588:3169–78
     [Google Scholar]
  166. 166. 
    Allen JA, Halverson-Tamboli RA, Rasenick MM 2006. Lipid raft microdomains and neurotransmitter signalling. Nat. Rev. Neurosci. 8:128–40
     [Google Scholar]
  167. 167. 
    Kimchi O, Veatch SL, Machta BB 2018. Ion channels can be allosterically regulated by membrane domains near a de-mixing critical point. J. Gen. Physiol. 150:1769–77
     [Google Scholar]
  168. 168. 
    Villar VM, Cuevas S, Zheng XX, Jose PA 2016. Localization and signaling of GPCRs in lipid rafts. G Protein-Coupled Receptors: Signaling, Trafficking and Regulation AK Shukla 3–23 Cambridge, MA: Academic
     [Google Scholar]
  169. 169. 
    Bukiya AN, Blank PS, Rosenhouse-Dantsker A 2019. Cholesterol intake and statin use regulate neuronal G protein-gated inwardly rectifying potassium channels. J. Lipid Res. 60:19–29
     [Google Scholar]
  170. 170. 
    Tennakoon M, Kankanamge D, Senarath K, Fasih Z, Karunarathne A 2019. Statins perturb Gβγ signaling and cell behavior in a Gγ subtype dependent manner. Mol. Pharmacol. 95:361–75
     [Google Scholar]
  171. 171. 
    Gomes I, Ayoub MA, Fujita W, Jaeger WC, Pfleger KDG, Devi LA 2016. G protein-coupled receptor heteromers. Annu. Rev. Pharmacol. Toxicol. 56:403–25
     [Google Scholar]
  172. 172. 
    Guidolin D, Marcoli M, Tortorella C, Maura G, Agnati LF 2019. Receptor-receptor interactions as a widespread phenomenon: novel targets for drug development?. Front. Endocrinol. 10:53
     [Google Scholar]
  173. 173. 
    Calebiro D, Koszegi Z. 2019. The subcellular dynamics of GPCR signaling. Mol. Cell. Endocrinol. 483:24–30
     [Google Scholar]
  174. 174. 
    Lyman E, Hsieh CL, Eggeling C 2018. From dynamics to membrane organization: Experimental breakthroughs occasion a “modeling manifesto.''. Biophys. J. 115:595–604
     [Google Scholar]
  175. 175. 
    Calebiro D, Sungkaworn T. 2018. Single-molecule imaging of GPCR interactions. Trends Pharmacol. Sci. 39:109–22
     [Google Scholar]
  176. 176. 
    Marrink SJ, Corradi V, Souza PCT, Ingólfsson HI, Tieleman DP, Sansom MSP 2019. Computational modeling of realistic cell membranes. Chem. Rev. 119:96184–226
     [Google Scholar]
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Lipid-Dependent Regulation of Ion Channels and G Protein–Coupled Receptors: Insights from Structures and Simulations
Annual Review of Pharmacology and Toxicology 60, 31 (2020); https://doi.org/10.1146/annurev-pharmtox-010919-023411
/content/journals/10.1146/annurev-pharmtox-010919-023411
/content/journals/10.1146/annurev-pharmtox-010919-023411
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