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Molecular Modeling of the Full-length Human TRPV1 Channel in Closed and Desensitized States

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Abstract

The transient receptor potential vanilloid subtype 1 (TRPV1) is a member of the TRP family gated by vanilloids, heat, and protons. Structurally, TRPV1 subunits have a modular architecture underlying different functionalities, namely stimuli recognition, channel gating, ion selectivity, subunit oligomerization, and regulation by intracellular signaling molecules. Considering modular organization and recent structural information in the ion channel field, we have modeled a full-length TRPV1 by assembly of its major modules: the cytosolic N-terminal, C-terminal, and membrane-spanning region. For N-terminal, we used the ankyrin repeat structure fused with the N-end segment. The membrane domain was modeled with the structure of the eukaryotic, voltage-gated Kv1.2 K+ channel. The C-terminus was cast using the coordinates of HCN channels. The extensive structure–function data available for TRPV1 was used to validate the models in terms of the location of molecular determinants of function in the structure. Additionally, the current information allowed the modeling of the vanilloid receptor in the closed and desensitized states. The closed state shows the N-terminal module highly exposed and accessible to adenosine triphosphate and the C-terminal accessible to phosphoinositides. In contrast, the desensitized state depicts the N-terminal and C-terminal modules close together, compatible with an interaction mediated by Ca2+–calmodulin complex. These models identify potential previously unrecognized intra- and interdomain interactions that may play an important functional role. Although the molecular models should be taken with caution, they provide a helpful tool that yields testable hypothesis that further our understanding on ion channels work in terms of underlying protein structure.

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References

  • Adamian L, Liang J (2006) Prediction of transmembrane helix orientation in polytopic membrane proteins. BMC Struct Biol 6:13

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Bhave G, Zhu W, Wang H, Brasier DJ, Oxford GS, Gereau RW (2002) cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation. Neuron 35:721–731

    Article  PubMed  CAS  Google Scholar 

  • Bhave G, Hu HJ, Glauner KS, Zhu W, Wang H, Brasier DJ, Oxford GS, Gereau RW (2003) Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1). Proc Natl Acad Sci USA 100:12480–12485

    Article  PubMed  CAS  Google Scholar 

  • Brauchi S, Orta G, Mascayano C, Salazar M, Raddatz N, Urbina H, Rosenmann E, Gonzalez-Nilo F, Latorre R (2007) Dissection of the components for PIP2 activation and thermosensation in TRP channels. Proc Natl Acad Sci USA 104:10246–10251

    Article  PubMed  CAS  Google Scholar 

  • Caterina MJ, Julius D (2001) The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci 24:487–517

    Article  PubMed  CAS  Google Scholar 

  • Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824

    Article  PubMed  CAS  Google Scholar 

  • Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313

    Article  PubMed  CAS  Google Scholar 

  • Chang C, Ray A, Swaan P (2005) In silico strategies for modeling membrane transporter function. Drug Discov Today 10:663–671

    Article  PubMed  CAS  Google Scholar 

  • Cromer BA, McIntyre P (2008) Painful toxins acting at TRPV1. Toxicon 51:163–173

    Article  PubMed  CAS  Google Scholar 

  • Elofsson A, von Heijne G (2007) Membrane protein structure: prediction vs reality. Annu Rev Biochem 76:125–140

    Article  PubMed  CAS  Google Scholar 

  • Ferrer-Montiel A, Garcia-Martinez C, Morenilla-Palao C, Garcia-Sanz N, Fernandez-Carvajal A, Fernandez-Ballester G, Planells-Cases R (2004) Molecular architecture of the vanilloid receptor. Insights for drug design. Eur J Biochem 271:1820–1826

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Martinez C, Morenilla-Palao C, Planells-Cases R, Merino JM, Ferrer-Montiel A (2000) Identification of an aspartic residue in the P-loop of the vanilloid receptor that modulates pore properties. J Biol Chem 275:32552–32558

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Martinez C, Humet M, Planells-Cases R, Gomis A, Caprini M, Viana F, De La PE, Sanchez-Baeza F, Carbonell T, De FC, Perez-Paya E, Belmonte C, Messeguer A, Ferrer-Montiel A (2002) Attenuation of thermal nociception and hyperalgesia by VR1 blockers. Proc Natl Acad Sci USA 99:2374–2379

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Sanz N, Fernandez-Carvajal A, Morenilla-Palao C, Planells-Cases R, Fajardo-Sanchez E, Fernandez-Ballester G, Ferrer-Montiel A (2004) Identification of a tetramerization domain in the C terminus of the vanilloid receptor. J Neurosci 24:5307–5314

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Sanz N, Valente P, Gomis A, Fernandez-Carvajal A, Fernandez-Ballester G, Viana F, Belmonte C, Ferrer-Montiel A (2007) A role of the transient receptor potential domain of vanilloid receptor I in channel gating. J Neurosci 27:11641–11650

    Article  PubMed  CAS  Google Scholar 

  • Gavva NR, Klionsky L, Qu Y, Shi L, Tamir R, Edenson S, Zhang TJ, Viswanadhan VN, Toth A, Pearce LV, Vanderah TW, Porreca F, Blumberg PM, Lile J, Sun Y, Wild K, Louis JC, Treanor JJ (2004) Molecular determinants of vanilloid sensitivity in TRPV1. J Biol Chem 279:20283–20295

    Article  PubMed  CAS  Google Scholar 

  • Gonnet GH, Cohen MA, Benner SA (1992) Exhaustive matching of the entire protein sequence database. Science 256:1443–1445

    Article  PubMed  CAS  Google Scholar 

  • Guerois R, Nielsen JE, Serrano L (2002) Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J Mol Biol 320:369–387

    Article  PubMed  CAS  Google Scholar 

  • Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723

    Article  PubMed  CAS  Google Scholar 

  • Hall TA (1999) BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 41:95–98

    CAS  Google Scholar 

  • Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38

    Article  PubMed  CAS  Google Scholar 

  • Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ (2002) p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36:57–68

    Article  PubMed  CAS  Google Scholar 

  • Jin X, Morsy N, Winston J, Pasricha PJ, Garrett K, Akbarali HI (2004) Modulation of TRPV1 by nonreceptor tyrosine kinase, c-Src kinase. Am J Physiol Cell Physiol 287:C558–C563

    Article  PubMed  CAS  Google Scholar 

  • Johnson DM, Garrett EM, Rutter R, Bonnert TP, Gao YD, Middleton RE, Sutton KG (2006) Functional mapping of the transient receptor potential vanilloid 1 intracellular binding site. Mol Pharmacol 70:1005–1012

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Jordt SE, Tominaga M, Julius D (2000) Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci USA 97:8134–8139

    Article  PubMed  CAS  Google Scholar 

  • Jung J, Lee SY, Hwang SW, Cho H, Shin J, Kang YS, Kim S, Oh U (2002) Agonist recognition sites in the cytosolic tails of vanilloid receptor 1. J Biol Chem 277:44448–44454

    Article  PubMed  CAS  Google Scholar 

  • Jung J, Shin JS, Lee SY, Hwang SW, Koo J, Cho H, Oh U (2004) Phosphorylation of vanilloid receptor 1 by Ca2+/calmodulin-dependent kinase II regulates its vanilloid binding. J Biol Chem 279:7048–7054

    Article  PubMed  CAS  Google Scholar 

  • Krogh A, Larsson B, von HG, Sonnhammer EL (2001) Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J Mol Biol 305:567–580

    Article  PubMed  CAS  Google Scholar 

  • Kwak J, Wang MH, Hwang SW, Kim TY, Lee SY, Oh U (2000) Intracellular ATP increases capsaicin-activated channel activity by interacting with nucleotide-binding domains. J Neurosci 20:8298–8304

    PubMed  CAS  Google Scholar 

  • Labarga A, Valentin F, Anderson M, Lopez R (2007) Web services at the European bioinformatics institute. Nucleic Acids Res 35:W6–W11

    Article  PubMed  Google Scholar 

  • Laskowski RA, Rullmannn JA, MacArthur MW, Kaptein R, Thornton JM (1996) AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR 8:477–486

    Article  PubMed  CAS  Google Scholar 

  • Latorre R, Brauchi S, Orta G, Zaelzer C, Vargas G (2007) ThermoTRP channels as modular proteins with allosteric gating. Cell Calcium 42:427–438

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Liu B, Zhang C, Qin F (2005) Functional recovery from desensitization of vanilloid receptor TRPV1 requires resynthesis of phosphatidylinositol 4,5-bisphosphate. J Neurosci 25:4835–4843

    Article  PubMed  CAS  Google Scholar 

  • Long SB, Campbell EB, MacKinnon R (2005) Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science 309:903–908

    Article  PubMed  CAS  Google Scholar 

  • Long SB, Tao X, Campbell EB, MacKinnon R (2007) Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature 450:376–382

    Article  PubMed  CAS  Google Scholar 

  • Mackerell AD Jr, Feig M, Brooks CL III (2004) Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J Comput Chem 25:1400–1415

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Minor DL Jr (2007) The neurobiologist’s guide to structural biology: a primer on why macromolecular structure matters and how to evaluate structural data. Neuron 54:511–533

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Montell C, Birnbaumer L, Flockerzi V (2002) The TRP channels, a remarkably functional family. Cell 108:595–598

    Article  PubMed  CAS  Google Scholar 

  • Morenilla-Palao C, Planells-Cases R, Garcia-Sanz N, Ferrer-Montiel A (2004) Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity. J Biol Chem 279:25665–25672

    Article  PubMed  CAS  Google Scholar 

  • Numazaki M, Tominaga T, Takeuchi K, Murayama N, Toyooka H, Tominaga M (2003) Structural determinant of TRPV1 desensitization interacts with calmodulin. Proc Natl Acad Sci USA 100:8002–8006

    Article  PubMed  CAS  Google Scholar 

  • Pedersen SF, Owsianik G, Nilius B (2005) TRP channels: an overview. Cell Calcium 38:233–252

    Article  PubMed  CAS  Google Scholar 

  • Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kale L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802

    Article  PubMed  CAS  Google Scholar 

  • Premkumar LS, Ahern GP (2000) Induction of vanilloid receptor channel activity by protein kinase C. Nature 408:985–990

    Article  PubMed  CAS  Google Scholar 

  • Prescott ED, Julius D (2003) A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science 300:1284–1288

    Article  PubMed  CAS  Google Scholar 

  • Ramsey IS, Delling M, Clapham DE (2006) An introduction to TRP channels. Annu Rev Physiol 68:619–647

    Article  PubMed  CAS  Google Scholar 

  • Rosenbaum T, Gordon-Shaag A, Munari M, Gordon SE (2004) Ca2+/calmodulin modulates TRPV1 activation by capsaicin. J Gen Physiol 123:53–62

    Article  PubMed  CAS  Google Scholar 

  • Ryu S, Liu B, Yao J, Fu Q, Qin F (2007) Uncoupling proton activation of vanilloid receptor TRPV1. J Neurosci 27:12797–12807

    Article  PubMed  CAS  Google Scholar 

  • Schwede T, Kopp J, Guex N, Peitsch MC (2003) SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Res 31:3381–3385

    Article  PubMed  CAS  Google Scholar 

  • Schymkowitz J, Borg J, Stricher F, Nys R, Rousseau F, Serrano L (2005) The FoldX Web server: an online force field. Nucleic Acids Res 33:W382–W388

    Article  PubMed  CAS  Google Scholar 

  • Stein AT, Ufret-Vincenty CA, Hua L, Santana LF, Gordon SE (2006) Phosphoinositide 3-kinase binds to TRPV1 and mediates NGF-stimulated TRPV1 trafficking to the plasma membrane. J Gen Physiol 128:509–522

    Article  PubMed  CAS  Google Scholar 

  • Tominaga M, Tominaga T (2005) Structure and function of TRPV1. Pflugers Arch 451:143–150

    Article  PubMed  CAS  Google Scholar 

  • Valente P, Garcia-Sanz N, Gomis A, Fernandez-Carvajal A, Fernandez-Ballester G, Viana F, Belmonte C, Ferrer-Montiel A (2008) Identification of molecular determinants of channel gating in the transient receptor potential box of vanilloid receptor I. FASEB J 22:3298–3309

    Article  PubMed  CAS  Google Scholar 

  • Venkatachalam K, Montell C (2007) TRP channels. Annu Rev Biochem 76:387–417

    Article  PubMed  CAS  Google Scholar 

  • Voets T, Droogmans G, Wissenbach U, Janssens A, Flockerzi V, Nilius B (2004) The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 430:748–754

    Article  PubMed  CAS  Google Scholar 

  • Voets T, Owsianik G, Janssens A, Talavera K, Nilius B (2007) TRPM8 voltage sensor mutants reveal a mechanism for integrating thermal and chemical stimuli. Nat Chem Biol 3:174–182

    Article  PubMed  CAS  Google Scholar 

  • Vriend G (1990) WHAT IF: a molecular modeling and drug design program. J Mol Graph 8:52–56

    Article  PubMed  CAS  Google Scholar 

  • Welch JM, Simon SA, Reinhart PH (2000) The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat. Proc Natl Acad Sci USA 97:13889–13894

    Article  PubMed  CAS  Google Scholar 

  • Wirkner K, Hognestad H, Jahnel R, Hucho F, Illes P (2005) Characterization of rat transient receptor potential vanilloid 1 receptors lacking the N-glycosylation site N604. Neuroreport 16:997–1001

    Article  PubMed  CAS  Google Scholar 

  • Yadav MK, Leman LJ, Price DJ, Brooks CL III, Stout CD, Ghadiri MR (2006) Coiled coils at the edge of configurational heterogeneity. Structural analyses of parallel and antiparallel homotetrameric coiled coils reveal configurational sensitivity to a single solvent-exposed amino acid substitution. Biochemistry 45:4463–4473

    Article  PubMed  CAS  Google Scholar 

  • Zagotta WN, Olivier NB, Black KD, Young EC, Olson R, Gouaux E (2003) Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature 425:200–205

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Huang J, McNaughton PA (2005) NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J 24:4211–4223

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the Spanish Ministry of Education and Science (MEC) (SAF2006-2580 to A. F. M.), the Fundación Ramón Areces (to A. F. M.), and the Generalitat Valenciana (GV/2007/025 to G. F. B.).

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  1. Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Avda. de la Universidad, s/n, 03202, Elche, Alicante, Spain

    G. Fernández-Ballester & A. Ferrer-Montiel

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  1. G. Fernández-Ballester
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  2. A. Ferrer-Montiel
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Correspondence to G. Fernández-Ballester.

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Fernández-Ballester, G., Ferrer-Montiel, A. Molecular Modeling of the Full-length Human TRPV1 Channel in Closed and Desensitized States. J Membrane Biol 223, 161–172 (2008). https://doi.org/10.1007/s00232-008-9123-7

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