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Molecular determinants of vanilloid sensitivity in TRPV1.
J Biol Chem. 2004 May 07; 279(19):20283-95.JB

Abstract

Vanilloid receptor 1 (TRPV1), a membrane-associated cation channel, is activated by the pungent vanilloid from chili peppers, capsaicin, and the ultra potent vanilloid from Euphorbia resinifera, resiniferatoxin (RTX), as well as by physical stimuli (heat and protons) and proposed endogenous ligands (anandamide, N-arachidonyldopamine, N-oleoyldopamine, and products of lipoxygenase). Only limited information is available in TRPV1 on the residues that contribute to vanilloid activation. Interestingly, rabbits have been suggested to be insensitive to capsaicin and have been shown to lack detectable [(3)H]RTX binding in membranes prepared from their dorsal root ganglia. We have cloned rabbit TRPV1 (oTRPV1) and report that it exhibits high homology to rat and human TRPV1. Like its mammalian orthologs, oTRPV1 is selectively expressed in sensory neurons and is sensitive to protons and heat activation but is 100-fold less sensitive to vanilloid activation than either rat or human. Here we identify key residues (Met(547) and Thr(550)) in transmembrane regions 3 and 4 (TM3/4) of rat and human TRPV1 that confer vanilloid sensitivity, [(3)H]RTX binding and competitive antagonist binding to rabbit TRPV1. We also show that these residues differentially affect ligand recognition as well as the assays of functional response versus ligand binding. Furthermore, these residues account for the reported pharmacological differences of RTX, PPAHV (phorbol 12-phenyl-acetate 13-acetate 20-homovanillate) and capsazepine between human and rat TRPV1. Based on our data we propose a model of the TM3/4 region of TRPV1 bound to capsaicin or RTX that may aid in the development of potent TRPV1 antagonists with utility in the treatment of sensory disorders.

Authors+Show Affiliations

Department of Neuroscience, Amgen Inc., MS 29-2 B, One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. ngavva@amgen.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

14996838

Citation

Gavva, Narender R., et al. "Molecular Determinants of Vanilloid Sensitivity in TRPV1." The Journal of Biological Chemistry, vol. 279, no. 19, 2004, pp. 20283-95.
Gavva NR, Klionsky L, Qu Y, et al. Molecular determinants of vanilloid sensitivity in TRPV1. J Biol Chem. 2004;279(19):20283-95.
Gavva, N. R., Klionsky, L., Qu, Y., Shi, L., Tamir, R., Edenson, S., Zhang, T. J., Viswanadhan, V. N., Toth, A., Pearce, L. V., Vanderah, T. W., Porreca, F., Blumberg, P. M., Lile, J., Sun, Y., Wild, K., Louis, J. C., & Treanor, J. J. (2004). Molecular determinants of vanilloid sensitivity in TRPV1. The Journal of Biological Chemistry, 279(19), 20283-95.
Gavva NR, et al. Molecular Determinants of Vanilloid Sensitivity in TRPV1. J Biol Chem. 2004 May 7;279(19):20283-95. PubMed PMID: 14996838.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular determinants of vanilloid sensitivity in TRPV1. AU - Gavva,Narender R, AU - Klionsky,Lana, AU - Qu,Yusheng, AU - Shi,Licheng, AU - Tamir,Rami, AU - Edenson,Steve, AU - Zhang,T J, AU - Viswanadhan,Vellarkad N, AU - Toth,Attila, AU - Pearce,Larry V, AU - Vanderah,Todd W, AU - Porreca,Frank, AU - Blumberg,Peter M, AU - Lile,Jack, AU - Sun,Yax, AU - Wild,Ken, AU - Louis,Jean-Claude, AU - Treanor,James J S, Y1 - 2004/03/02/ PY - 2004/3/5/pubmed PY - 2004/6/16/medline PY - 2004/3/5/entrez SP - 20283 EP - 95 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 279 IS - 19 N2 - Vanilloid receptor 1 (TRPV1), a membrane-associated cation channel, is activated by the pungent vanilloid from chili peppers, capsaicin, and the ultra potent vanilloid from Euphorbia resinifera, resiniferatoxin (RTX), as well as by physical stimuli (heat and protons) and proposed endogenous ligands (anandamide, N-arachidonyldopamine, N-oleoyldopamine, and products of lipoxygenase). Only limited information is available in TRPV1 on the residues that contribute to vanilloid activation. Interestingly, rabbits have been suggested to be insensitive to capsaicin and have been shown to lack detectable [(3)H]RTX binding in membranes prepared from their dorsal root ganglia. We have cloned rabbit TRPV1 (oTRPV1) and report that it exhibits high homology to rat and human TRPV1. Like its mammalian orthologs, oTRPV1 is selectively expressed in sensory neurons and is sensitive to protons and heat activation but is 100-fold less sensitive to vanilloid activation than either rat or human. Here we identify key residues (Met(547) and Thr(550)) in transmembrane regions 3 and 4 (TM3/4) of rat and human TRPV1 that confer vanilloid sensitivity, [(3)H]RTX binding and competitive antagonist binding to rabbit TRPV1. We also show that these residues differentially affect ligand recognition as well as the assays of functional response versus ligand binding. Furthermore, these residues account for the reported pharmacological differences of RTX, PPAHV (phorbol 12-phenyl-acetate 13-acetate 20-homovanillate) and capsazepine between human and rat TRPV1. Based on our data we propose a model of the TM3/4 region of TRPV1 bound to capsaicin or RTX that may aid in the development of potent TRPV1 antagonists with utility in the treatment of sensory disorders. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/14996838/Molecular_determinants_of_vanilloid_sensitivity_in_TRPV1_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=14996838 DB - PRIME DP - Unbound Medicine ER -