Understand spiciness: mechanism of TRPV1 channel activation by capsaicin

doi:10.1007/s13238-016-0353-7

Protein Cell

2017, Vol. 8

Issue (3) : 169-177 https://doi.org/10.1007/s13238-016-0353-7

REVIEW

Understand spiciness: mechanism of TRPV1 channel activation by capsaicin

Fan Yang,Jie Zheng(

)

Department of Physiology and Membrane Biology, University of California, Davis, CA 95616, USA

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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.

Keywords capsaicin TRPV1 ligand gating cryo-EM computation spiciness

Corresponding Author(s): Jie Zheng

Issue Date: 21 March 2017

Cite this article:

Fan Yang,Jie Zheng. Understand spiciness: mechanism of TRPV1 channel activation by capsaicin[J]. Protein Cell, 2017, 8(3): 169-177.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-016-0353-7
https://academic.hep.com.cn/pac/EN/Y2017/V8/I3/169

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. https://doi.org/10.1523/JNEUROSCI.0237-05.2005
2	Appendino G (2003) Halogenation of a capsaicin analogue leads to novel vanilloid TRPV1 receptor antagonists. Br J Pharmacol 139:1417–1424. https://doi.org/10.1038/sj.bjp.0705387
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. https://doi.org/10.1021/jm050139q
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. https://doi.org/10.1073/pnas.0702515104
5	Bevan S, Szolcsanyi J (1990) Sensory neuron-specific actions of capsaicin: mechanisms and applications. Trends Pharm Sci 11:330–333 https://doi.org/10.1016/0165-6147(90)90237-3
6	Bhutani M (2007) Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin Cancer Res 13:3024–3032. https://doi.org/10.1158/1078-0432.CCR-06-2575
7	Bohlen CJ (2010) A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell 141:834–845. https://doi.org/10.1016/j.cell.2010.03.052
8	Cao E, Liao M, Cheng Y, Julius D (2013) TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504:113–118. https://doi.org/10.1038/nature12823
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. https://doi.org/10.1085/jgp.201311025
10	Carnevale V, Rohacs T (2016) TRPV1: a target for rational drug design. Pharmaceuticals. https://doi.org/10.3390/ph9030052
11	Caterina MJ (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824. https://doi.org/10.1038/ 39807
12	Caterina MJ (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313 https://doi.org/10.1126/science.288.5464.306
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. https://doi.org/10.1085/jgp.200709731
14	Cheng W, Sun C, Zheng J (2010) Heteromerization of TRP channel subunits: extending functional diversity. Protein & Cell 1(9):802–810 https://doi.org/10.1007/s13238-010-0108-9
15	Cheng W (2012) Heteromeric heat-sensitive transient receptor potential channels exhibit distinct temperature and chemical response. J Biol Chem 287:7279–7288. https://doi.org/10.1074/jbc.M111. 305045
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. https://doi.org/10.1085/jgp. 201110724
17	Darre L, Domene C (2015) Binding of capsaicin to the TRPV1 Ion Channel. Mol Pharm 12:4454–4465. https://doi.org/10.1021/acs. molpharmaceut.5b00641
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. https://doi.org/10.1146/ annurev-biophys-062215-011034
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. https://doi.org/10.1073/pnas. 1517288113
20	Fernandez JA (2011) Voltage- and cold-dependent gating of single TRPM8 ion channels. J Gen Physiol 137:173–195. https://doi.org/10. 1085/jgp.201010498
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. https://doi.org/10.1007/s00232-008-9123-7
22	Ferrer-Montiel A (2004) Molecular architecture of the vanilloid receptor. Insights for drug design. Eur J Biochem 271:1820–1826. https://doi.org/10.1111/j.1432-1033.2004.04083.x
23	Fischer MJ (2014) Direct evidence for functional TRPV1/TRPA1 heteromers. Pflugers Arch Eur J Physiol 466:2229–2241. https://doi.org/10. 1007/s00424-014-1497-z
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. https://doi.org/10.1038/nature17964
25	Gavva NR (2004) Molecular determinants of vanilloid sensitivity in TRPV1. J Biol Chem 279:20283–20295. https://doi.org/10.1074/jbc. M312577200
26	Grosman C, Zhou M, Auerbach A (2000) Mapping the conformational wave of acetylcholine receptor channel gating. Nature 403:773–776. https://doi.org/10.1038/35001586
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. https://doi.org/10.1016/j. bpj.2015.02.013
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. https://doi.org/10.1016/S0006-3495(03)70022-8
29	Huynh KW (2016) Structure of the full-length TRPV2 channel by cryo-EM. Nat Commun 7:11130. https://doi.org/10.1038/ncomms11130
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. https://doi.org/10.1021/bi300279b
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. https://doi.org/10.1074/jbc.C600153200
32	Jordt SE, Julius D (2002) Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell 108:421–430 https://doi.org/10.1016/S0092-8674(02)00637-2
33	Julius D (2013) TRP channels and pain. Ann Rev Cell Dev Biol 29:355–384. https://doi.org/doi:10.1146/annurev-cellbio-101011-155833
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. https://doi.org/10.1085/jgp. 201210810
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. https://doi.org/10.1517/17460440802681300
36	Leaver-Fay A (2011)ROSETTA3: anobject-orientedsoftware suite for the simulation and design ofmacromolecules. MethodsEnzymol 487:545–574. https://doi.org/10.1016/B978-0-12-381270-4.00019-6
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. https://doi.org/10.1038/nature12822
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. <Date>2007.05.027</Date> https://doi.org/10.1016/j.neuron.
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 https://doi.org/10.1085/jgp.20028696
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 https://doi.org/10.1038/srep33827
41	Matta JA, Ahern GP (2007) Voltage is a partial activator of rat thermosensitive TRP channels. J Physiol 585:469–482. https://doi.org/10. 1113/jphysiol.2007.144287
42	McGann M (2012) FRED and HYBRID docking performance on standardized datasets. J Comput Aid Mol Des 26:897–906. https://doi.org/10.1007/s10822-012-9584-8
43	Mio K (2007) The TRPC3 channel has a large internal chamber surrounded by signal sensing antennas. J Mol Biol 367:373–383. https://doi.org/10.1016/j.jmb.2006.12.043
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. https://doi.org/10. 1073/pnas.0711835105
45	Montell C (2002) A unified nomenclature for the superfamily of TRP cation channels. Mol Cell 9:229–231 https://doi.org/10.1016/S1097-2765(02)00448-3
46	Moran MM, McAlexander MA, Biro T, Szallasi A (2011) Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov 10:601–620. https://doi.org/10.1038/nrd3456
47	Nelson EK, Dawson LE (1923) The constitution of capsaicin, the pungent principle of capsicum III. J Am Chem Soc 45:2179–2181. https://doi.org/10.1021/ja01662a023
48	Nilius B, Appendino G (2013) Spices: the savory and beneficial science of pungency. Rev Physiol Biochem Pharmacol 164:1–76. https://doi.org/10.1007/112_2013_11
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. https://doi.org/10.1371/journal.pone.0162543
51	Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D (2015) Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature. https://doi.org/10.1038/nature14367
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. https://doi.org/10. 1021/bi702109w
53	Piskorowski R, Aldrich RW (2002) Calcium activation of BK(Ca) potassium channels lacking the calcium bowl and RCK domains. Nature 420:499–502. https://doi.org/10.1038/nature01199
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. https://doi.org/10.1073/pnas.1405371111
55	Purohit P, Mitra A, Auerbach A (2007) A stepwise mechanism for acetylcholine receptor channel gating. Nature 446:930–933. https://doi.org/10.1038/nature05721
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 https://doi.org/10.1016/S0896-6273(00)80030-6
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. https://doi.org/10.1038/ nsmb.1633
59	Saotome K, Singh AK, Yelshanskaya MV, Sobolevsky AI (2016) Crystal structure of the epithelial calcium channel TRPV6. Nature 534:506–511. https://doi.org/10.1038/nature17975
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 https://doi.org/10.1016/S0022-2836(95)80064-6
61	Scoville WL (1912) Note on capsicums. J Am Pharm Assoc 1:1. https://doi.org/10.1002/jps.3080010520
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. https://doi.org/10.1007/s13238-013-3091-0
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. https://doi.org/10.1074/jbc.M109.090712
64	Siemens J (2006) Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature 444:208–212. https://doi.org/10.1038/ nature05285
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 https://doi.org/10.1085/jgp.113.5.621
66	Sunderman ER, Zagotta WN (1999b) Mechanism of allosteric modulation of rod cyclic nucleotide-gated channels. J Gen Physiol 113:601–620 https://doi.org/10.1085/jgp.113.5.601
67	Szallasi A (1994) The vanilloid (capsaicin) receptor: receptor types and species differences. Gen Pharmacol 25:223–243 https://doi.org/10.1016/0306-3623(94)90049-3
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. https://doi.org/10.1002/prot.22755
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 https://doi.org/10.1254/jjp.83.20
74	Tominaga M (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–543 https://doi.org/10.1016/S0896-6273(00)80564-4
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. https://doi.org/10.1073/pnas.1000357107
76	Yang F, Yarov-Yarovoy V, Zheng J (2013) Modeling temperaturedependent ion channel protein structural changes with rosetta. Biophys J 104:229a–230a. https://doi.org/10.1016/j.bpj.2012.11.1295
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. https://doi.org/10.1085/jgp. 201311024
78	Yang S (2015a) A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1. Nat Commun 6:8297. https://doi.org/10.1038/ncomms9297
79	Yang F (2015b) Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. Nat Chem Biol 11:518–524. https://doi.org/10.1038/nchembio.1835
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. https://doi.org/10.1073/pnas.1604180113
81	Yarov-Yarovoy V, Schonbrun J, Baker D (2006) Multipass membrane protein structure prediction using Rosetta. Proteins 62:1010–1025. https://doi.org/10.1002/prot.20817
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. https://doi.org/10.1073/pnas.1118434109
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. https://doi.org/10.1155/2015/983951
84	Zagotta WN (2003) Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature 425:200–205. https://doi.org/10.1038/nature01922
85	Zhang F (2016) Engineering vanilloid-sensitivity into the rat TRPV2 channel. eLife. https://doi.org/10.7554/eLife.16409
86	Zheng J (2013) Molecular mechanism of TRP channels. Compr Physiol 3:221–242. https://doi.org/10.1002/cphy.c120001
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. https://doi.org/10.1371/journal.pcbi.1001046
88	Zheng J, Ma L (2014) Structure and function of the thermoTRP channel pore. Curr Top Membr 74:233–257. https://doi.org/10.1016/B978-0-12-800181-3.00009-9
89	Zheng J, Trudeau MC (2015) Handbook of ion channels. CRC Press, Boca Raton https://doi.org/10.1201/b18027
90	Zubcevic L (2016) Cryo-electron microscopy structure of the TRPV2 ion channel. Nat Struct Mol Biol 23:180–186. https://doi.org/10. 1038/nsmb.3159

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