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Understand spiciness: mechanism of TRPV1 channel activation by capsaicin

  • Fan Yang ,
  • Jie Zheng
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  • Department of Physiology and Membrane Biology, University of California, Davis, CA 95616, USA

Received date: 22 Sep 2016

Accepted date: 22 Nov 2016

Published date: 21 Mar 2017

Copyright

2016 The Author(s) 2016. This article is published with open access at Springerlink.com and journal.hep.com.cn

Abstract

Capsaicin in chili peppers bestows the sensation of spiciness. Since the discovery of its receptor, transient receptor potential vanilloid 1 (TRPV1) ion channel, how capsaicin activates this channel has been under extensive investigation using a variety of experimental techniques including mutagenesis, patch-clamp recording, crystallography, cryo-electron microscopy, computational docking and molecular dynamic simulation. A framework of how capsaicin binds and activates TRPV1 has started to merge: capsaicin binds to a pocket formed by the channel’s transmembrane segments, where it takes a “tail-up, head-down” configuration. Binding is mediated by both hydrogen bonds and van der Waals interactions. Upon binding, capsaicin stabilizes the open state of TRPV1 by “pull-andcontact” with the S4-S5 linker. Understanding the ligand-host interaction will greatly facilitate pharmaceutical efforts to develop novel analgesics targeting TRPV1.

Cite this article

Fan Yang , Jie Zheng . Understand spiciness: mechanism of TRPV1 channel activation by capsaicin[J]. Protein & Cell, 2017 , 8(3) : 169 -177 . DOI: 10.1007/s13238-016-0353-7

1
Ahern GP, Brooks IM, Miyares RL, Wang XB (2005) Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling. J Neurosci Off J Soc Neurosci 25:5109–5116.

DOI

2
Appendino G (2003) Halogenation of a capsaicin analogue leads to novel vanilloid TRPV1 receptor antagonists. Br J Pharmacol 139:1417–1424.

DOI

3
Appendino G (2005) The taming of capsaicin. Reversal of the vanilloid activity of N-acylvanillamines by aromatic iodination. J Med Chem 48:4663–4669.

DOI

4
Barth P,Schonbrun J, Baker D(2007)Toward high-resolution prediction and design of transmembrane helical protein structures. Proc Natl Acad Sci USA 104:15682–15687.

DOI

5
Bevan S, Szolcsanyi J (1990) Sensory neuron-specific actions of capsaicin: mechanisms and applications. Trends Pharm Sci 11:330–333

DOI

6
Bhutani M (2007) Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin Cancer Res 13:3024–3032.

DOI

7
Bohlen CJ (2010) A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell 141:834–845.

DOI

8
Cao E, Liao M, Cheng Y, Julius D (2013) TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504:113–118.

DOI

9
Cao X, Ma L, Yang F, Wang K, Zheng J (2014) Divalent cations potentiate TRPV1 channel by lowering the heat activation threshold. J Gen Physiol 143:75–90.

DOI

10
Carnevale V, Rohacs T (2016) TRPV1: a target for rational drug design. Pharmaceuticals.

DOI

11
Caterina MJ (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824.

DOI

12
Caterina MJ (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313

DOI

13
Cheng W, Yang F, Takanishi CL, Zheng J(2007) Thermosensitive TRPV channel subunits coassemble into heteromeric channels with intermediate conductance and gating properties. J Gen Physiol 129:191–207.

DOI

14
Cheng W, Sun C, Zheng J (2010) Heteromerization of TRP channel subunits: extending functional diversity. Protein & Cell 1(9):802–810

DOI

15
Cheng W (2012) Heteromeric heat-sensitive transient receptor potential channels exhibit distinct temperature and chemical response. J Biol Chem 287:7279–7288.

DOI

16
Cui Y (2012) Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations. J Gen Physiol 139:273–283.

DOI

17
Darre L, Domene C (2015) Binding of capsaicin to the TRPV1 Ion Channel. Mol Pharm 12:4454–4465.

DOI

18
Diaz-Franulic I, Poblete H, Mino-Galaz G, Gonzalez C, Latorre R (2016) Allosterism and structure in thermally activated transient receptor potential channels. Ann Rev Biophys.

DOI

19
Elokely K (2016) Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin. Proc Natl Acad Sci USA 113:E137–145.

DOI

20
Fernandez JA (2011) Voltage- and cold-dependent gating of single TRPM8 ion channels. J Gen Physiol 137:173–195.

DOI

21
Fernandez-Ballester G, Ferrer-Montiel A (2008) Molecular modeling of the full-length human TRPV1 channel in closed and desensitized states. J Membr Biol 223:161–172.

DOI

22
Ferrer-Montiel A (2004) Molecular architecture of the vanilloid receptor. Insights for drug design. Eur J Biochem 271:1820–1826.

DOI

23
Fischer MJ (2014) Direct evidence for functional TRPV1/TRPA1 heteromers. Pflugers Arch Eur J Physiol 466:2229–2241.

DOI

24
Gao Y, Cao E, Julius D, Cheng Y (2016) TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature 534:347–351.

DOI

25
Gavva NR (2004) Molecular determinants of vanilloid sensitivity in TRPV1. J Biol Chem 279:20283–20295.

DOI

26
Grosman C, Zhou M, Auerbach A (2000) Mapping the conformational wave of acetylcholine receptor channel gating. Nature 403:773–776.

DOI

27
Hanson SM, Newstead S, Swartz KJ, Sansom MS (2015) Capsaicin interaction with TRPV1 channels in a lipid bilayer: molecular dynamics simulation. Biophys J 108:1425–1434.

DOI

28
Hui K, Liu B, Qin F (2003) Capsaicin activation of the pain receptor, VR1: multiple open states from both partial and full binding. Biophys J 84:2957–2968.

DOI

29
Huynh KW (2016) Structure of the full-length TRPV2 channel by cryo-EM. Nat Commun 7:11130.

DOI

30
Inada H, Procko E, Sotomayor M, Gaudet R(2012) Structural and biochemical consequences of disease-causing mutations in the ankyrin repeat domain of the human TRPV4 channel. Biochemistry 51:6195–6206.

DOI

31
Jin X, Touhey J, Gaudet R (2006) Structure of the N-terminal ankyrin repeat domain of the TRPV2 ion channel. J Biol Chem 281:25006–25010.

DOI

32
Jordt SE, Julius D (2002) Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell 108:421–430

DOI

33
Julius D (2013) TRP channels and pain. Ann Rev Cell Dev Biol 29:355–384.

DOI

34
Lau SY, Procko E, Gaudet R (2012) Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel. J Gen Physiol 140:541–555.

DOI

35
Lazar J, Gharat L, Khairathkar-Joshi N, Blumberg PM, Szallasi A (2009) Screening TRPV1 antagonists for the treatment of pain: lessons learned over a decade. Expert Opin Drug Discov 4:159–180.

DOI

36
Leaver-Fay A (2011)ROSETTA3: anobject-orientedsoftware suite for the simulation and design ofmacromolecules. MethodsEnzymol 487:545–574.

DOI

37
Liao M, Cao E, Julius D, Cheng Y (2013) Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504:107–112.

DOI

38
Lishko PV, Procko E, Jin X, Phelps CB, Gaudet R (2007) The ankyrin repeats of TRPV1 bind multiple ligands and modulate channel sensitivity. Neuron 54:905–918. lt;Date>2007.05.027</Date>

DOI

39
Lu Z, Klem AM, Ramu Y (2002) Coupling between voltage sensors and activation gate in voltage-gated K+ channels. J Gen Physiol 120:663–676

DOI

40
Ma L, Yang F, Vu S, Zheng J (2016) Exploring functional roles of TRPV1 intracellular domains with unstructured peptide-insertion screening. Sci Rep 6:33827

DOI

41
Matta JA, Ahern GP (2007) Voltage is a partial activator of rat thermosensitive TRP channels. J Physiol 585:469–482.

DOI

42
McGann M (2012) FRED and HYBRID docking performance on standardized datasets. J Comput Aid Mol Des 26:897–906.

DOI

43
Mio K (2007) The TRPC3 channel has a large internal chamber surrounded by signal sensing antennas. J Mol Biol 367:373–383.

DOI

44
Moiseenkova-Bell VY, Stanciu LA, Serysheva II, Tobe BJ, Wensel TG (2008) Structure of TRPV1 channel revealed by electron cryomicroscopy. Proc Natl Acad Sci USA 105:7451–7455.

DOI

45
Montell C (2002) A unified nomenclature for the superfamily of TRP cation channels. Mol Cell 9:229–231

DOI

46
Moran MM, McAlexander MA, Biro T, Szallasi A (2011) Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov 10:601–620.

DOI

47
Nelson EK, Dawson LE (1923) The constitution of capsaicin, the pungent principle of capsicum III. J Am Chem Soc 45:2179–2181.

DOI

48
Nilius B, Appendino G (2013) Spices: the savory and beneficial science of pungency. Rev Physiol Biochem Pharmacol 164:1–76.

DOI

49
Oh U, Hwang SW, Kim D (1996) Capsaicin activates a nonselective cation channel in cultured neonatal rat dorsal root ganglion neurons. J Neurosci Off J Soc Neurosci 16:1659–1667

50
Ohbuchi K (2016) Detailed analysis of the binding mode of vanilloids to transient receptor potential vanilloid type I (TRPV1) by a mutational and computational study. PloS ONE 11: e0162543.

DOI

51
Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D (2015) Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature.

DOI

52
Phelps CB, Huang RJ, Lishko PV, Wang RR, Gaudet R (2008) Structural analyses of the ankyrin repeat domain of TRPV6 and related TRPV ion channels. Biochemistry 47:2476–2484.

DOI

53
Piskorowski R, Aldrich RW (2002) Calcium activation of BK(Ca) potassium channels lacking the calcium bowl and RCK domains. Nature 420:499–502.

DOI

54
Puljung MC, DeBerg HA, Zagotta WN, Stoll S (2014) Double electron-electron resonance reveals cAMP-induced conformational change in HCN channels. Proc Natl Acad Sci USA 111:9816–9821.

DOI

55
Purohit P, Mitra A, Auerbach A (2007) A stepwise mechanism for acetylcholine receptor channel gating. Nature 446:930–933.

DOI

56
Ranganathan R, Lewis JH, MacKinnon R (1996) Spatial localization of the K+ channel selectivity filter by mutant cycle-based structure analysis. Neuron 16:131–139

DOI

57
Sakmann B, Neher E (2009) Single-channel recording, 2nd edn. Springer, New York

58
Salazar H (2009) Structural determinants of gating in the TRPV1 channel. Nat Struct Mol Biol 16:704–710.

DOI

59
Saotome K, Singh AK, Yelshanskaya MV, Sobolevsky AI (2016) Crystal structure of the epithelial calcium channel TRPV6. Nature 534:506–511.

DOI

60
Schreiber G, Fersht AR (1995) Energetics of protein-protein interactions: analysis of the barnase-barstar interface by single mutations and double mutant cycles. J Mol Biol 248:478–486

DOI

61
Scoville WL (1912) Note on capsicums. J Am Pharm Assoc 1:1.

DOI

62
Shi DJ, Ye S, Cao X, Zhang R, Wang K (2013) Crystal structure of the N-terminal ankyrin repeat domain of TRPV3 reveals unique conformation of finger 3 loop critical for channel function. Prot Cell 4:942–950.

DOI

63
Shigematsu H, Sokabe T, Danev R, Tominaga M, Nagayama K (2010) A, 3.5-nm structure of rat TRPV4 cation channel revealed by Zernike phase-contrast cryoelectron microscopy. J Biol Chem 285:11210–11218.

DOI

64
Siemens J (2006) Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature 444:208–212.

DOI

65
Sunderman ER, Zagotta WN (1999a) Sequence of events underlying the allosteric transition of rod cyclic nucleotide-gated channels. J Gen Physiol 113:621–640

DOI

66
Sunderman ER, Zagotta WN (1999b) Mechanism of allosteric modulation of rod cyclic nucleotide-gated channels. J Gen Physiol 113:601–620

DOI

67
Szallasi A (1994) The vanilloid (capsaicin) receptor: receptor types and species differences. Gen Pharmacol 25:223–243

DOI

68
Szallasi A, Blumberg PM (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–212

69
Szolcsanyi J, Jancso-Gabor A (1975) Sensory effects of capsaicin congeners I. Relationship between chemical structure and painproducing potency of pungent agents. Arzneimittelforschung 25:1877–1881

70
Szolcsanyi J, Jancso-Gabor A (1976) Sensory effects of capsaicin congeners. Part II: Importance of chemical structure and pungency in desensitizing activity of capsaicin-type compounds. Arzneimittelforschung 26:33–37

71
Tekpinar M, Zheng W (2010) Predicting order of conformational changes during protein conformational transitions using an interpolated elastic network model. Proteins 78:2469–2481.

DOI

72
Thresh JC (1876) Isolation of capsaicin. Pharm J Trans 6:941–947

73
Tominaga M, Julius D (2000) Capsaicin receptor in the pain pathway. Jpn J Pharm 83:20–24

DOI

74
Tominaga M (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–543

DOI

75
Yang F, Cui Y,Wang K, Zheng J (2010) Thermosensitive TRP channel pore turret is part of the temperature activation pathway. Proc Natl Acad Sci USA 107:7083–7088.

DOI

76
Yang F, Yarov-Yarovoy V, Zheng J (2013) Modeling temperaturedependent ion channel protein structural changes with rosetta. Biophys J 104:229a–230a.

DOI

77
Yang F, Ma L, Cao X, Wang K, Zheng J (2014) Divalent cations activate TRPV1 through promoting conformational change of the extracellular region. J Gen Physiol 143:91–103.

DOI

78
Yang S (2015a) A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1. Nat Commun 6:8297.

DOI

79
Yang F (2015b) Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. Nat Chem Biol 11:518–524.

DOI

80
Yang F, Vu S, Yarov-Yarovoy V, Zheng J (2016) Rational design and validation of a vanilloid-sensitive TRPV2 ion channel. Proc Natl Acad Sci USA.

DOI

81
Yarov-Yarovoy V, Schonbrun J, Baker D (2006) Multipass membrane protein structure prediction using Rosetta. Proteins 62:1010–1025.

DOI

82
Yarov-Yarovoy V (2012) Structural basis for gating charge movement in the voltage sensor of a sodium channel. Proc Natl Acad Sci USA 109:E93–102.

DOI

83
Ye XY, Ling QZ, Chen SJ (2015) Identification of a potential target of capsaicin by computational target fishing. Evid Based Complement Altern Med 2015:983951.

DOI

84
Zagotta WN (2003) Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature 425:200–205.

DOI

85
Zhang F (2016) Engineering vanilloid-sensitivity into the rat TRPV2 channel. eLife.

DOI

86
Zheng J (2013) Molecular mechanism of TRP channels. Compr Physiol 3:221–242.

DOI

87
Zheng W, Auerbach A (2011) Decrypting the sequence of structural events during the gating transition of pentameric ligand-gated ion channels based on an interpolated elastic network model. PLoS Comput Biol 7:e1001046.

DOI

88
Zheng J, Ma L (2014) Structure and function of the thermoTRP channel pore. Curr Top Membr 74:233–257.

DOI

89
Zheng J, Trudeau MC (2015) Handbook of ion channels. CRC Press, Boca Raton

DOI

90
Zubcevic L (2016) Cryo-electron microscopy structure of the TRPV2 ion channel. Nat Struct Mol Biol 23:180–186.

DOI

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