Understand spiciness: mechanism of TRPV1 channel activation by capsaicin
Received date: 22 Sep 2016
Accepted date: 22 Nov 2016
Published date: 21 Mar 2017
Copyright
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.
Key words: capsaicin; TRPV1; ligand gating; cryo-EM; computation; spiciness
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.
|
2 |
Appendino G
|
3 |
Appendino G
|
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.
|
5 |
Bevan S, Szolcsanyi J (1990) Sensory neuron-specific actions of capsaicin: mechanisms and applications. Trends Pharm Sci 11:330–333
|
6 |
Bhutani M
|
7 |
Bohlen CJ
|
8 |
Cao E, Liao M, Cheng Y, Julius D (2013) TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504:113–118.
|
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.
|
10 |
Carnevale V, Rohacs T (2016) TRPV1: a target for rational drug design. Pharmaceuticals.
|
11 |
Caterina MJ
|
12 |
Caterina MJ
|
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.
|
14 |
Cheng W, Sun C, Zheng J (2010) Heteromerization of TRP channel subunits: extending functional diversity. Protein & Cell 1(9):802–810
|
15 |
Cheng W
|
16 |
Cui Y
|
17 |
Darre L, Domene C (2015) Binding of capsaicin to the TRPV1 Ion Channel. Mol Pharm 12:4454–4465.
|
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.
|
19 |
Elokely K
|
20 |
Fernandez JA
|
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.
|
22 |
Ferrer-Montiel A
|
23 |
Fischer MJ
|
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.
|
25 |
Gavva NR
|
26 |
Grosman C, Zhou M, Auerbach A (2000) Mapping the conformational wave of acetylcholine receptor channel gating. Nature 403:773–776.
|
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.
|
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.
|
29 |
Huynh KW
|
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.
|
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.
|
32 |
Jordt SE, Julius D (2002) Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell 108:421–430
|
33 |
Julius D (2013) TRP channels and pain. Ann Rev Cell Dev Biol 29:355–384.
|
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.
|
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.
|
36 |
Leaver-Fay A
|
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.
|
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>
|
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
|
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
|
41 |
Matta JA, Ahern GP (2007) Voltage is a partial activator of rat thermosensitive TRP channels. J Physiol 585:469–482.
|
42 |
McGann M (2012) FRED and HYBRID docking performance on standardized datasets. J Comput Aid Mol Des 26:897–906.
|
43 |
Mio K
|
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.
|
45 |
Montell C
|
46 |
Moran MM, McAlexander MA, Biro T, Szallasi A (2011) Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov 10:601–620.
|
47 |
Nelson EK, Dawson LE (1923) The constitution of capsaicin, the pungent principle of capsicum III. J Am Chem Soc 45:2179–2181.
|
48 |
Nilius B, Appendino G (2013) Spices: the savory and beneficial science of pungency. Rev Physiol Biochem Pharmacol 164:1–76.
|
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
|
51 |
Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D (2015) Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature.
|
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.
|
53 |
Piskorowski R, Aldrich RW (2002) Calcium activation of BK(Ca) potassium channels lacking the calcium bowl and RCK domains. Nature 420:499–502.
|
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.
|
55 |
Purohit P, Mitra A, Auerbach A (2007) A stepwise mechanism for acetylcholine receptor channel gating. Nature 446:930–933.
|
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
|
57 |
Sakmann B, Neher E (2009) Single-channel recording, 2nd edn. Springer, New York
|
58 |
Salazar H
|
59 |
Saotome K, Singh AK, Yelshanskaya MV, Sobolevsky AI (2016) Crystal structure of the epithelial calcium channel TRPV6. Nature 534:506–511.
|
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
|
61 |
Scoville WL (1912) Note on capsicums. J Am Pharm Assoc 1:1.
|
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.
|
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.
|
64 |
Siemens J
|
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
|
66 |
Sunderman ER, Zagotta WN (1999b) Mechanism of allosteric modulation of rod cyclic nucleotide-gated channels. J Gen Physiol 113:601–620
|
67 |
Szallasi A (1994) The vanilloid (capsaicin) receptor: receptor types and species differences. Gen Pharmacol 25:223–243
|
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.
|
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
|
74 |
Tominaga M
|
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.
|
76 |
Yang F, Yarov-Yarovoy V, Zheng J (2013) Modeling temperaturedependent ion channel protein structural changes with rosetta. Biophys J 104:229a–230a.
|
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.
|
78 |
Yang S
|
79 |
Yang F
|
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.
|
81 |
Yarov-Yarovoy V, Schonbrun J, Baker D (2006) Multipass membrane protein structure prediction using Rosetta. Proteins 62:1010–1025.
|
82 |
Yarov-Yarovoy V
|
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.
|
84 |
Zagotta WN
|
85 |
Zhang F
|
86 |
Zheng J (2013) Molecular mechanism of TRP channels. Compr Physiol 3:221–242.
|
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.
|
88 |
Zheng J, Ma L (2014) Structure and function of the thermoTRP channel pore. Curr Top Membr 74:233–257.
|
89 |
Zheng J, Trudeau MC (2015) Handbook of ion channels. CRC Press, Boca Raton
|
90 |
Zubcevic L
|
/
〈 | 〉 |