Skip to main content
SpringerLink
Log in

Cholesterol-Dependent Gating Effects on Ion Channels

  • Chapter
  • First Online:
Book cover Cholesterol Modulation of Protein Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1115))

Abstract

Biomembranes separate a live cell from its environment and keep it in an off-equilibrium, steady state. They contain both phospholipids and nonphospholipids, depending on whether there are phosphate groups in the headgroup regions. Cholesterol (CHOL) is one type of nonphospholipids, and one of the most abundant lipid molecules in humans. Its content in plasma membranes and intracellular membranes varies and is tightly regulated. Voltage-gated ion channels are universally present in every cell and are fairly diversified in the eukaryotic domain of life. Our lipid-dependent gating hypothesis postulates that the controlled switch of the voltage-sensor domains (VSDs) in a voltage-gated potassium (Kv) channel between the “down” and the “up” state (gating) is sensitive to the ratio of phospholipids:nonphospholipids in the annular layer around the channel. High CHOL content is found to exert strong inhibitory effects on Kv channels. Such effects have been observed in in vitro membranes, cultured cells, and animal models for cholesterol metabolic defects. Thermodynamic analysis of the CHOL-dependent gating suggests that the inhibitory effects of CHOL result from collective interactions between annular CHOL molecules and the channel, which appear to be a more generic principle behind the CHOL effects on other ion channels and transporters. We will review the recent progress in the CHOL-dependent gating of voltage-gated ion channels, discuss the current technical limitations, and then expand briefly the learned principles to other ion channels that are known to be sensitive to the CHOL–channel interactions.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Powl AM, East JM, Lee AG. Anionic phospholipids affect the rate and extent of flux through the mechanosensitive channel of large conductance MscL. Biochemistry. 2008;47(14):4317–28.

    Article  PubMed  CAS  Google Scholar 

  2. Powl AM, East JM, Lee AG. Lipid-protein interactions studied by introduction of a tryptophan residue: the mechanosensitive channel MscL. Biochemistry. 2003;42(48):14306–17.

    Article  PubMed  CAS  Google Scholar 

  3. Zaydman MA, et al. Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening. Proc Natl Acad Sci U S A. 2013;110(32):13180–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Whorton MR, MacKinnon R. X-ray structure of the mammalian GIRK2-betagamma G-protein complex. Nature. 2013;498(7453):190–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Rittenhouse AR. PIP2 PIP2 hooray for maxi K+. J Gen Physiol. 2008;132(1):5–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Lee J, et al. PIP2 activates TRPV5 and releases its inhibition by intracellular Mg2+. J Gen Physiol. 2005;126(5):439–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Xiao J, Zhen XG, Yang J. Localization of PIP2 activation gate in inward rectifier K+ channels. Nat Neurosci. 2003;6(8):811–8.

    Article  PubMed  CAS  Google Scholar 

  8. Zaydman MA, Cui J. PIP2 regulation of KCNQ channels: biophysical and molecular mechanisms for lipid modulation of voltage-dependent gating. Front Physiol. 2014;5:195.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Furst O, D’Avanzo N. Isoform dependent regulation of human HCN channels by cholesterol. Sci Rep. 2015;5:14270.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Valiyaveetil FI, Zhou Y, MacKinnon R. Lipids in the structure, folding, and function of the KcsA K+ channel. Biochemistry. 2002;41(35):10771–7.

    Article  PubMed  CAS  Google Scholar 

  11. Valiyaveetil FI, et al. Glycine as a D-amino acid surrogate in the K(+)-selectivity filter. Proc Natl Acad Sci U S A. 2004;101(49):17045–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Long SB, et al. Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature. 2007;450(7168):376–82.

    Article  PubMed  CAS  Google Scholar 

  13. Dowhan W, Bogdanov M. Lipid-dependent membrane protein topogenesis. Annu Rev Biochem. 2009;78:515–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Zhang M, Mileykovskaya E, Dowhan W. Cardiolipin is essential for organization of complexes III and IV into a supercomplex in intact yeast mitochondria. J Biol Chem. 2005;280(33):29403–8.

    Article  PubMed  CAS  Google Scholar 

  15. Mileykovskaya E, Zhang M, Dowhan W. Cardiolipin in energy transducing membranes. Biochemistry (Mosc). 2005;70(2):154–8.

    Article  CAS  Google Scholar 

  16. Alberts B, et al. Molecular biology of the cell. 5th ed. New York: Garland Science; 2007.

    Book  Google Scholar 

  17. Palfreyman M, Jorgensen EM. PKC defends crown against Munc13. Neuron. 2007;54(2):179–80.

    Article  PubMed  CAS  Google Scholar 

  18. de Jong AP, et al. Phosphorylation of synaptotagmin-1 controls a post-priming step in PKC-dependent presynaptic plasticity. Proc Natl Acad Sci U S A. 2016;113(18):5095–100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Kalwa H, et al. Phospholipase C epsilon (PLCepsilon) induced TRPC6 activation: a common but redundant mechanism in primary podocytes. J Cell Physiol. 2015;230(6):1389–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Zhang X, Trebak M. Transient receptor potential canonical 7: a diacylglycerol-activated non-selective cation channel. Handb Exp Pharmacol. 2014;222:189–204.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Itsuki K, et al. PLC-mediated PI(4,5)P2 hydrolysis regulates activation and inactivation of TRPC6/7 channels. J Gen Physiol. 2014;143(2):183–201.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Venkatachalam K, Zheng F, Gill DL. Control of TRPC and store-operated channels by protein kinase C. Novartis Found Symp. 2004;258:172–85; discussion 185-8, 263-6.

    PubMed  CAS  Google Scholar 

  23. Schmitt S, Castelvetri LC, Simons M. Metabolism and functions of lipids in myelin. Biochim Biophys Acta. 2015;1851(8):999–1005.

    Article  PubMed  CAS  Google Scholar 

  24. Smaby JM, et al. Cholesterol-induced interfacial area condensations of galactosylceramides and sphingomyelins with identical acyl chains. Biochemistry. 1996;35(18):5696–704.

    Article  PubMed  CAS  Google Scholar 

  25. Di Biase A, Salvati S, Serlupi Crescenzi G. Lipid profile of rat myelin subfractions. Neurochem Res. 1990;15(5):519–22.

    Article  PubMed  Google Scholar 

  26. Hill WG, et al. Isolation and characterization of the Xenopus oocyte plasma membrane: a new method for studying activity of water and solute transporters. Am J Physiol Renal Physiol. 2005;289(1):F217–24.

    Article  PubMed  CAS  Google Scholar 

  27. Sadler SE. Low-density caveolae-like membrane from Xenopus laevis oocytes is enriched in Ras. J Cell Biochem. 2001;83(1):21–32.

    Article  PubMed  CAS  Google Scholar 

  28. Orth M, Bellosta S. Cholesterol: its regulation and role in central nervous system disorders. Cholesterol. 2012;2012:292598.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Levitan I, Singh DK, Rosenhouse-Dantsker A. Cholesterol binding to ion channels. Front Physiol. 2014;5:65.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Li Q, et al. Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain. Nat Struct Mol Biol. 2014;21(3):244–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Long SB, Campbell EB, Mackinnon R. Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science. 2005;309(5736):897–903.

    Article  PubMed  CAS  Google Scholar 

  32. Hille B. Ion channels of excitable membranes. 3rd ed. Sunderland: Sinauer Associates; 2001.

    Google Scholar 

  33. Shribman S, et al. Voltage-gated potassium channelopathy: an expanding spectrum of clinical phenotypes. BMJ Case Rep. 2013;2013:bcr2012007742.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Poolos NP, Johnston D. Dendritic ion channelopathy in acquired epilepsy. Epilepsia. 2012;53(Suppl 9):32–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Baig SM, et al. Loss of Ca(v)1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nat Neurosci. 2011;14(1):77–84.

    Article  PubMed  CAS  Google Scholar 

  36. Xie G, et al. A new Kv1.2 channelopathy underlying cerebellar ataxia. J Biol Chem. 2010;285(42):32160–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Tremblay J, Hamet P. Genetics of pain, opioids, and opioid responsiveness. Metabolism. 2010;59(Suppl 1):S5–8.

    Article  PubMed  CAS  Google Scholar 

  38. Pietrobon D. CaV2.1 channelopathies. Pflugers Arch. 2010;460(2):375–93.

    Article  PubMed  CAS  Google Scholar 

  39. Rajakulendran S, et al. Episodic ataxia type 1: a neuronal potassium channelopathy. Neurotherapeutics. 2007;4(2):258–66.

    Article  PubMed  CAS  Google Scholar 

  40. Kordasiewicz HB, Gomez CM. Molecular pathogenesis of spinocerebellar ataxia type 6. Neurotherapeutics. 2007;4(2):285–94.

    Article  PubMed  CAS  Google Scholar 

  41. Howard RJ, et al. Structural insight into KCNQ (Kv7) channel assembly and channelopathy. Neuron. 2007;53(5):663–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Estevez M. Invertebrate modeling of a migraine channelopathy. Headache. 2006;46(Suppl 1):S25–31.

    Article  PubMed  Google Scholar 

  43. Cox JJ, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444(7121):894–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Bjerregaard P, Jahangir A, Gussak I. Targeted therapy for short QT syndrome. Expert Opin Ther Targets. 2006;10(3):393–400.

    Article  PubMed  CAS  Google Scholar 

  45. Poolos NP. The h-channel: a potential channelopathy in epilepsy? Epilepsy Behav. 2005;7(1):51–6.

    Article  PubMed  Google Scholar 

  46. Tao X, et al. A gating charge transfer center in voltage sensors. Science. 2010;328:67–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Kintzer AF, Stroud RM. Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana. Nature. 2016;531(7593):258–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Guo J, et al. Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana. Nature. 2016;531(7593):196–201.

    Article  PubMed  CAS  Google Scholar 

  49. Payandeh J, et al. The crystal structure of a voltage-gated sodium channel. Nature. 2011;475(7356):353–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Wang W, MacKinnon R. Cryo-EM structure of the open human ether-a-go-go-related K(+) channel hERG. Cell. 2017;169(3):422–430.e10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Lee CH, MacKinnon R. Structures of the human HCN1 hyperpolarization-activated channel. Cell. 2017;168(1-2):111–120.e11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Hite RK, MacKinnon R. Structural titration of Slo2.2, a Na+−dependent K+ channel. Cell. 2017;168(3):390–399.e11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Whicher JR, MacKinnon R. Structure of the voltage-gated K(+) channel Eag1 reveals an alternative voltage sensing mechanism. Science. 2016;353(6300):664–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Wu J, et al. Structure of the voltage-gated calcium channel Cav1.1 complex. Science. 2015;350(6267):aad2395.

    Article  PubMed  CAS  Google Scholar 

  55. Sun J, MacKinnon R. Cryo-EM structure of a KCNQ1/CaM complex reveals insights into congenital long QT syndrome. Cell. 2017;169(6):1042–1050.e9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Vargas E, et al. An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations. J Gen Physiol. 2012;140(6):587–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Villalba-Galea CA, et al. Charge movement of a voltage-sensitive fluorescent protein. Biophys J. 2009;96(2):L19–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Vargas E, Bezanilla F, Roux B. In search of a consensus model of the resting state of a voltage-sensing domain. Neuron. 2011;72(5):713–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Villalba-Galea CA, et al. S4-based voltage sensors have three major conformations. Proc Natl Acad Sci U S A. 2008;105(46):17600–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Chanda B, Bezanilla F. A common pathway for charge transport through voltage-sensing domains. Neuron. 2008;57(3):345–51.

    Article  PubMed  CAS  Google Scholar 

  61. Bezanilla F. The voltage-sensor structure in a voltage-gated channel. Trends Biochem Sci. 2005;30(4):166–8.

    Article  PubMed  CAS  Google Scholar 

  62. Sigg D, Bezanilla F. A physical model of potassium channel activation: from energy landscape to gating kinetics. Biophys J. 2003;84(6):3703–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Bezanilla F, Perozo E. The voltage sensor and the gate in ion channels. Adv Protein Chem. 2003;63:211–41.

    Article  PubMed  CAS  Google Scholar 

  64. Bezanilla F. Voltage sensor movements. J Gen Physiol. 2002;120(4):465–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Bezanilla F. The voltage sensor in voltage-dependent ion channels. Physiol Rev. 2000;80(2):555–92.

    Article  PubMed  CAS  Google Scholar 

  66. Papazian DM, Bezanilla F. Voltage-dependent activation of ion channels. Adv Neurol. 1999;79:481–91.

    PubMed  CAS  Google Scholar 

  67. Cha A, Bezanilla F. Structural implications of fluorescence quenching in the Shaker K+ channel. J Gen Physiol. 1998;112(4):391–408.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Sigg D, Bezanilla F. Total charge movement per channel. The relation between gating charge displacement and the voltage sensitivity of activation. J Gen Physiol. 1997;109(1):27–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Cha A, Bezanilla F. Characterizing voltage-dependent conformational changes in the Shaker K+ channel with fluorescence. Neuron. 1997;19(5):1127–40.

    Article  PubMed  CAS  Google Scholar 

  70. Bezanilla F, Stefani E. Voltage-dependent gating of ionic channels. Annu Rev Biophys Biomol Struct. 1994;23:819–46.

    Article  PubMed  CAS  Google Scholar 

  71. Shenkel S, Bezanilla F. Patch recordings from the electrocytes of electrophorus. Na channel gating currents. J Gen Physiol. 1991;98(3):465–78.

    Article  PubMed  CAS  Google Scholar 

  72. Lee SY, et al. Structure of the KvAP voltage-dependent K+ channel and its dependence on the lipid membrane. Proc Natl Acad Sci U S A. 2005;102(43):15441–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Jiang QX, Wang DN, MacKinnon R. Electron microscopic analysis of KvAP voltage-dependent K+ channels in an open conformation. Nature. 2004;430(7001):806–10.

    Article  PubMed  CAS  Google Scholar 

  74. Jiang Y, et al. The principle of gating charge movement in a voltage-dependent K+ channel. Nature. 2003;423(6935):42–8.

    Article  PubMed  CAS  Google Scholar 

  75. Jiang Y, et al. X-ray structure of a voltage-dependent K+ channel. Nature. 2003;423(6935):33–41.

    Article  PubMed  CAS  Google Scholar 

  76. Ahern CA, et al. Electrostatic contributions of aromatic residues in the local anesthetic receptor of voltage-gated sodium channels. Circ Res. 2008;102(1):86–94.

    Article  PubMed  CAS  Google Scholar 

  77. Horn R. How ion channels sense membrane potential. Proc Natl Acad Sci U S A. 2005;102(14):4929–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Ahern CA, Horn R. Focused electric field across the voltage sensor of potassium channels. Neuron. 2005;48(1):25–9.

    Article  PubMed  CAS  Google Scholar 

  79. Ahern CA, Horn R. Specificity of charge-carrying residues in the voltage sensor of potassium channels. J Gen Physiol. 2004;123(3):205–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Horn R. Coupled movements in voltage-gated ion channels. J Gen Physiol. 2002;120(4):449–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Horn R. A new twist in the saga of charge movement in voltage-dependent ion channels. Neuron. 2000;25(3):511–4.

    Article  PubMed  CAS  Google Scholar 

  82. Horn R. Conversation between voltage sensors and gates of ion channels. Biochemistry. 2000;39(51):15653–8.

    Article  PubMed  CAS  Google Scholar 

  83. Yang N, Horn R. Evidence for voltage-dependent S4 movement in sodium channels. Neuron. 1995;15(1):213–8.

    Article  PubMed  CAS  Google Scholar 

  84. Li Q, et al. Structural basis of lipid-driven conformational transitions in the KvAP voltage-sensing domain. Nat Struct Mol Biol. 2014;21(2):160–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Tang L, et al. Structural basis for Ca2+ selectivity of a voltage-gated calcium channel. Nature. 2014;505(7481):56–61.

    Article  PubMed  CAS  Google Scholar 

  86. Catterall WA. Structure and function of voltage-gated sodium channels at atomic resolution. Exp Physiol. 2014;99(1):35–51.

    Article  PubMed  CAS  Google Scholar 

  87. Payandeh J, et al. Crystal structure of a voltage-gated sodium channel in two potentially inactivated states. Nature. 2012;486(7401):135–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Catterall WA. Voltage-gated calcium channels. Cold Spring Harb Perspect Biol. 2011;3(8):a003947.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Catterall WA. Ion channel voltage sensors: structure, function, and pathophysiology. Neuron. 2010;67(6):915–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Yarov-Yarovoy V, Baker D, Catterall WA. Voltage sensor conformations in the open and closed states in ROSETTA structural models of K(+) channels. Proc Natl Acad Sci U S A. 2006;103(19):7292–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Sokolov S, Scheuer T, Catterall WA. Ion permeation through a voltage- sensitive gating pore in brain sodium channels having voltage sensor mutations. Neuron. 2005;47(2):183–9.

    Article  PubMed  CAS  Google Scholar 

  92. Yu FH, Catterall WA. Overview of the voltage-gated sodium channel family. Genome Biol. 2003;4(3):24.

    Article  Google Scholar 

  93. Catterall WA. Structure and function of voltage-gated ion channels. Annu Rev Biochem. 1995;64:493–531.

    Article  PubMed  CAS  Google Scholar 

  94. Catterall WA. Molecular properties of voltage-sensitive sodium and calcium channels. Braz J Med Biol Res. 1988;21(6):1129–44.

    PubMed  CAS  Google Scholar 

  95. Tombola F, Ulbrich MH, Isacoff EY. Architecture and gating of Hv1 proton channels. J Physiol. 2009;587(Pt 22):5325–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Pathak MM, et al. Closing in on the resting state of the Shaker K(+) channel. Neuron. 2007;56(1):124–40.

    Article  PubMed  CAS  Google Scholar 

  97. Tombola F, Pathak MM, Isacoff EY. How does voltage open an ion channel? Annu Rev Cell Dev Biol. 2006;22:23–52.

    Article  PubMed  CAS  Google Scholar 

  98. Tombola F, Pathak MM, Isacoff EY. Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores. Neuron. 2005;45(3):379–88.

    Article  PubMed  CAS  Google Scholar 

  99. Gandhi CS, Isacoff EY. Molecular models of voltage sensing. J Gen Physiol. 2002;120(4):455–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Mannuzzu LM, Isacoff EY. Independence and cooperativity in rearrangements of a potassium channel voltage sensor revealed by single subunit fluorescence. J Gen Physiol. 2000;115(3):257–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Mannuzzu LM, Moronne MM, Isacoff EY. Direct physical measure of conformational rearrangement underlying potassium channel gating. Science. 1996;271(5246):213–6.

    Article  PubMed  CAS  Google Scholar 

  102. Larsson HP, et al. Transmembrane movement of the shaker K+ channel S4. Neuron. 1996;16(2):387–97.

    Article  PubMed  CAS  Google Scholar 

  103. Heginbotham L, et al. Mutations in the K+ channel signature sequence. Biophys J. 1994;66(4):1061–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Heginbotham L, MacKinnon R. Conduction properties of the cloned Shaker K+ channel. Biophys J. 1993;65(5):2089–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Aggarwal SK, MacKinnon R. Contribution of the S4 segment to gating charge in the Shaker K+ channel. Neuron. 1996;16(6):1169–77.

    Article  PubMed  CAS  Google Scholar 

  106. Starace DM, Bezanilla F. Histidine scanning mutagenesis of basic residues of the S4 segment of the shaker k+ channel. J Gen Physiol. 2001;117(5):469–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Seoh SA, et al. Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel. Neuron. 1996;16(6):1159–67.

    Article  PubMed  CAS  Google Scholar 

  108. Islas LD, Sigworth FJ. Electrostatics and the gating pore of Shaker potassium channels. J Gen Physiol. 2001;117(1):69–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Islas LD, Sigworth FJ. Voltage sensitivity and gating charge in Shaker and Shab family potassium channels. J Gen Physiol. 1999;114(5):723–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Schoppa NE, Sigworth FJ. Activation of Shaker potassium channels. III. An activation gating model for wild-type and V2 mutant channels. J Gen Physiol. 1998;111(2):313–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Schoppa NE, et al. The size of gating charge in wild-type and mutant Shaker potassium channels. Science. 1992;255(5052):1712–5.

    Article  PubMed  CAS  Google Scholar 

  112. Zhou Y, MacKinnon R. Ion binding affinity in the cavity of the KcsA potassium channel. Biochemistry. 2004;43(17):4978–82.

    Article  PubMed  CAS  Google Scholar 

  113. Zhou Y, MacKinnon R. The occupancy of ions in the K+ selectivity filter: charge balance and coupling of ion binding to a protein conformational change underlie high conduction rates. J Mol Biol. 2003;333(5):965–75.

    Article  PubMed  CAS  Google Scholar 

  114. Zhang X, et al. Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel. Nature. 2012;486(7401):130–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Takeshita K, et al. X-ray crystal structure of voltage-gated proton channel. Nat Struct Mol Biol. 2014;21(4):352–7.

    Article  PubMed  CAS  Google Scholar 

  116. Clayton GM, et al. Combining electron crystallography and X-ray crystallography to study the MlotiK1 cyclic nucleotide-regulated potassium channel. J Struct Biol. 2009;167(3):220–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Tao X, Hite RK, MacKinnon R. Cryo-EM structure of the open high-conductance Ca2+-activated K+ channel. Nature. 2017;541(7635):46–51.

    Article  PubMed  CAS  Google Scholar 

  118. Hite RK, Tao X, MacKinnon R. Structural basis for gating the high-conductance Ca2+-activated K+ channel. Nature. 2017;541(7635):52–7.

    Article  PubMed  CAS  Google Scholar 

  119. Fox PD, Loftus RJ, Tamkun MM. Regulation of Kv2.1 K(+) conductance by cell surface channel density. J Neurosci. 2013;33(3):1259–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. O’Connell KM, Loftus R, Tamkun MM. Localization-dependent activity of the Kv2.1 delayed-rectifier K+ channel. Proc Natl Acad Sci U S A. 2010;107(27):12351–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. O’Connell KM, Tamkun MM. Targeting of voltage-gated potassium channel isoforms to distinct cell surface microdomains. J Cell Sci. 2005;118(Pt 10):2155–66.

    Article  PubMed  CAS  Google Scholar 

  122. Martens JR, et al. Isoform-specific localization of voltage-gated K+ channels to distinct lipid raft populations. Targeting of Kv1.5 to caveolae. J Biol Chem. 2001;276(11):8409–14.

    Article  PubMed  CAS  Google Scholar 

  123. Purcell EK, et al. Cholesterol influences voltage-gated calcium channels and BK-type potassium channels in auditory hair cells. PLoS One. 2011;6(10):e26289.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Huang CW, Wu YJ, Wu SN. Modification of activation kinetics of delayed rectifier K+ currents and neuronal excitability by methyl-beta-cyclodextrin. Neuroscience. 2011;176:431–41.

    Article  PubMed  CAS  Google Scholar 

  125. Finol-Urdaneta RK, et al. Modulation of KvAP unitary conductance and gating by 1-alkanols and other surface active agents. Biophys J. 2010;98(5):762–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Guo J, et al. Effects of cholesterol levels on the excitability of rat hippocampal neurons. Mol Membr Biol. 2008;25(3):216–23.

    Article  PubMed  CAS  Google Scholar 

  127. Pottosin II, et al. Methyl-beta-cyclodextrin reversibly alters the gating of lipid rafts-associated Kv1.3 channels in Jurkat T lymphocytes. Pflugers Arch. 2007;454(2):235–44.

    Article  PubMed  CAS  Google Scholar 

  128. Balijepalli RC, et al. Kv11.1 (ERG1) K+ channels localize in cholesterol and sphingolipid enriched membranes and are modulated by membrane cholesterol. Channels (Austin). 2007;1(4):263–72.

    Article  Google Scholar 

  129. Abi-Char J, et al. Membrane cholesterol modulates Kv1.5 potassium channel distribution and function in rat cardiomyocytes. J Physiol. 2007;582(Pt 3):1205–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Xia F, et al. Disruption of pancreatic beta-cell lipid rafts modifies Kv2.1 channel gating and insulin exocytosis. J Biol Chem. 2004;279(23):24685–91.

    Article  PubMed  CAS  Google Scholar 

  131. Pouvreau S, et al. Membrane cholesterol modulates dihydropyridine receptor function in mice fetal skeletal muscle cells. J Physiol. 2004;555(Pt 2):365–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Hajdu P, et al. Cholesterol modifies the gating of Kv1.3 in human T lymphocytes. Pflugers Arch. 2003;445(6):674–82.

    Article  PubMed  CAS  Google Scholar 

  133. Rudakova E, et al. Localization of Kv4.2 and KChIP2 in lipid rafts and modulation of outward K+ currents by membrane cholesterol content in rat left ventricular myocytes. Pflugers Arch. 2015;467(2):299–309.

    Article  PubMed  CAS  Google Scholar 

  134. Bowles DK, et al. Hypercholesterolemia inhibits L-type calcium current in coronary macro-, not microcirculation. J Appl Physiol (1985). 2004;96(6):2240–8.

    Article  CAS  Google Scholar 

  135. Heaps CL, Tharp DL, Bowles DK. Hypercholesterolemia abolishes voltage-dependent K+ channel contribution to adenosine-mediated relaxation in porcine coronary arterioles. Am J Physiol Heart Circ Physiol. 2005;288(2):H568–76.

    Article  PubMed  CAS  Google Scholar 

  136. Balajthy A, et al. 7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome. Pflugers Arch. 2016;468:1403.

    Article  PubMed  CAS  Google Scholar 

  137. Chun YS, et al. Cholesterol modulates ion channels via down-regulation of phosphatidylinositol 4,5-bisphosphate. J Neurochem. 2010;112(5):1286–94.

    Article  PubMed  CAS  Google Scholar 

  138. Coyan FC, et al. A long QT mutation substitutes cholesterol for phosphatidylinositol-4,5-bisphosphate in KCNQ1 channel regulation. PLoS One. 2014;9(3):e93255.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Heaps CL, et al. Effects of exercise training and hypercholesterolemia on adenosine activation of voltage-dependent K+ channels in coronary arterioles. J Appl Physiol. 2008;105(6):1761–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Balijepalli SY, et al. Mechanism of loss of Kv11.1 K+ current in mutant T421M-Kv11.1-expressing rat ventricular myocytes: interaction of trafficking and gating. Circulation. 2012;126(24):2809–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Xu Y, Ramu Y, Lu Z. Removal of phospho-head groups of membrane lipids immobilizes voltage sensors of K+ channels. Nature. 2008;451(7180):826–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Ramu Y, Xu Y, Lu Z. Enzymatic activation of voltage-gated potassium channels. Nature. 2006;442(7103):696–9.

    Article  PubMed  CAS  Google Scholar 

  143. Zheng H, et al. Lipid-dependent gating of a voltage-gated potassium channel. Nat Commun. 2011;2:250.

    Article  PubMed  CAS  Google Scholar 

  144. Jiang Q-X, Gonen T. The influence of lipids on voltage-gated ion channels. Curr Opin Struct Biol. 2012;22:529–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Gantz SC, Bean BP. Cell-autonomous excitation of midbrain dopamine neurons by endocannabinoid-dependent lipid signaling. Neuron. 2017;93(6):1375–1387.e2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Randich AM, et al. Biochemical and structural analysis of the hyperpolarization-activated K(+) channel MVP. Biochemistry. 2014;53(10):1627–36.

    Article  PubMed  CAS  Google Scholar 

  147. Amsalem M, et al. Membrane cholesterol depletion as a trigger of Nav1.9 channel-mediated inflammatory pain. EMBO J. 2018;37(8):e97349.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Calhoun JD, Isom LL. The role of non-pore-forming beta subunits in physiology and pathophysiology of voltage-gated sodium channels. Handb Exp Pharmacol. 2014;221:51–89.

    Article  PubMed  CAS  Google Scholar 

  149. Hofmann F, Belkacemi A, Flockerzi V. Emerging alternative functions for the auxiliary subunits of the voltage-gated calcium channels. Curr Mol Pharmacol. 2015;8(2):162–8.

    Article  PubMed  CAS  Google Scholar 

  150. Liu SL, et al. Orthogonal lipid sensors identify transbilayer asymmetry of plasma membrane cholesterol. Nat Chem Biol. 2017;13(3):268–74.

    Article  PubMed  CAS  Google Scholar 

  151. Zheng H, et al. bSUM: a bead-supported unilamellar membrane system facilitating unidirectional insertion of membrane proteins into giant vesicles. J Gen Physiol. 2016;147(1):77–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Lingwood D, Simons K. Lipid rafts as a membrane-organizing principle. Science. 2010;327(5961):46–50.

    Article  PubMed  CAS  Google Scholar 

  153. Kaiser HJ, et al. Order of lipid phases in model and plasma membranes. Proc Natl Acad Sci U S A. 2009;106(39):16645–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Coskun U, Simons K. Membrane rafting: from apical sorting to phase segregation. FEBS Lett. 2009;28:28.

    Google Scholar 

  155. Anderson RG. The caveolae membrane system. Annu Rev Biochem. 1998;67:199–225.

    Article  PubMed  CAS  Google Scholar 

  156. Anderson RG. Transendothelial movement and caveolae. Nat Biotechnol. 2008;26(4):380–1; author reply 381-2.

    Article  PubMed  CAS  Google Scholar 

  157. Mizuno H, et al. Fluorescent probes for superresolution imaging of lipid domains on the plasma membrane. Chem Sci. 2011;2:1548.

    Article  CAS  Google Scholar 

  158. Klitzing HA, Weber PK, Kraft ML. Secondary ion mass spectrometry imaging of biological membranes at high spatial resolution. Methods Mol Biol. 2013;950:483–501.

    PubMed  CAS  Google Scholar 

  159. Kraft ML. Sphingolipid organization in the plasma membrane and the mechanisms that influence it. Front Cell Dev Biol. 2016;4:154.

    PubMed  Google Scholar 

  160. Richard M, Raquel F. Non-raft forming sphingomyelin-cholesterol mixtures. Chem Phys Lipids. 2004;132(1):37–46.

    Article  CAS  Google Scholar 

  161. Dietrich C, et al. Lipid rafts reconstituted in model membranes. Biophys J. 2001;80(3):1417–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Wang L, Bose PS, Sigworth FJ. Using cryo-EM to measure the dipole potential of a lipid membrane. Proc Natl Acad Sci U S A. 2006;103(49):18528–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Nyholm TK, et al. Construction of a DOPC/PSM/cholesterol phase diagram based on the fluorescence properties of trans-parinaric acid. Langmuir. 2011;27:8339.

    Article  PubMed  CAS  Google Scholar 

  164. Kolter T, Sandhoff K. Sphingolipid metabolism diseases. Biochim Biophys Acta. 2006;1758(12):2057–79.

    Article  PubMed  CAS  Google Scholar 

  165. Cheng SH. Gene therapy for the neurological manifestations in lysosomal storage disorders. J Lipid Res. 2014;55:1827.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Bolsover FE, et al. Cognitive dysfunction and depression in Fabry disease: a systematic review. J Inherit Metab Dis. 2014;37(2):177–87.

    Article  PubMed  Google Scholar 

  167. Bellettato CM, Scarpa M. Pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis. 2010;33(4):347–62.

    Article  PubMed  CAS  Google Scholar 

  168. Millard EE, et al. The sterol-sensing domain of the Niemann-Pick C1 (NPC1) protein regulates trafficking of low density lipoprotein cholesterol. J Biol Chem. 2005;280(31):28581–90.

    Article  PubMed  CAS  Google Scholar 

  169. Millard EE, et al. Niemann-pick type C1 (NPC1) overexpression alters cellular cholesterol homeostasis. J Biol Chem. 2000;275(49):38445–51.

    Article  PubMed  CAS  Google Scholar 

  170. Praggastis M, et al. A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele. J Neurosci. 2015;35(21):8091–106.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Andersson M, et al. Structural dynamics of the S4 voltage-sensor helix in lipid bilayers lacking phosphate groups. J Phys Chem B. 2011;115(27):8732–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. O’Connell KM, Martens JR, Tamkun MM. Localization of ion channels to lipid Raft domains within the cardiovascular system. Trends Cardiovasc Med. 2004;14(2):37–42.

    Article  PubMed  CAS  Google Scholar 

  173. Martens JR, O’Connell K, Tamkun M. Targeting of ion channels to membrane microdomains: localization of KV channels to lipid rafts. Trends Pharmacol Sci. 2004;25(1):16–21.

    Article  PubMed  CAS  Google Scholar 

  174. Martens JR, et al. Differential targeting of Shaker-like potassium channels to lipid rafts. J Biol Chem. 2000;275(11):7443–6.

    Article  PubMed  CAS  Google Scholar 

  175. Bichenkov E, Ellingson JS. Temporal and quantitative expression of the myelin-associated lipids, ethanolamine plasmalogen, galactocerebroside, and sulfatide, in the differentiating CG-4 glial cell line. Neurochem Res. 1999;24(12):1549–56.

    Article  PubMed  CAS  Google Scholar 

  176. Unwin N. Segregation of lipids near acetylcholine-receptor channels imaged by cryo-EM. IUCrJ. 2017;4(Pt 4):393–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Sun J, Comeau JF, Baenziger JE. Probing the structure of the uncoupled nicotinic acetylcholine receptor. Biochim Biophys Acta. 2017;1859(2):146–54.

    Article  CAS  Google Scholar 

  178. Brannigan G. Direct interactions of cholesterol with pentameric ligand-gated ion channels: testable hypotheses from computational predictions. Curr Top Membr. 2017;80:163–86.

    Article  PubMed  CAS  Google Scholar 

  179. daCosta CJ, et al. A distinct mechanism for activating uncoupled nicotinic acetylcholine receptors. Nat Chem Biol. 2013;9(11):701–7.

    Article  PubMed  CAS  Google Scholar 

  180. Barrantes FJ. Cell-surface translational dynamics of nicotinic acetylcholine receptors. Front Synaptic Neurosci. 2014;6:25.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Gao Y, et al. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature. 2016;534(7607):347–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

Over the years, the main body of research in my laboratory on lipid-dependent gating has been funded by NIH (R01GM111367, R01GM093271 & R01GM088745), AHA (12IRG9400019), CF Foundation (JIANG15G0), Welch Foundation (I-1684), and CPRIT (RP120474). I am indebted to many colleagues in the ion channel field and in lipid research for their valuable suggestions and advice. I have tried my best to cover most, if not all, published work closely related to CHOL-dependent gating effects on ion channels, and would apologize to those whose work is not cited here.

Author information

Authors and Affiliations

  1. Department of Microbiology and Cell Science, IFAS, University of Florida, Gainesville, FL, USA

    Qiu-Xing Jiang

Authors
  1. Qiu-Xing Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qiu-Xing Jiang .

Editor information

Editors and Affiliations

  1. Department of Chemistry, University of Illinois, Chicago, IL, USA

    Avia Rosenhouse-Dantsker

  2. The University of Tennessee Health Science Center, Memphis, TN, USA

    Anna N. Bukiya

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Jiang, QX. (2019). Cholesterol-Dependent Gating Effects on Ion Channels. In: Rosenhouse-Dantsker, A., Bukiya, A.N. (eds) Cholesterol Modulation of Protein Function. Advances in Experimental Medicine and Biology, vol 1115. Springer, Cham. https://doi.org/10.1007/978-3-030-04278-3_8

Download citation

Publish with us

Policies and ethics

Search

Navigation