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J. Biol. Chem., Vol. 279, Issue 19, 20283-20295, May 7, 2004

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Molecular Determinants of Vanilloid Sensitivity in TRPV1^*

Narender R. Gavva, Lana Klionsky, Yusheng Qu, Licheng Shi, Rami Tamir, Steve Edenson, T. J. Zhang, Vellarkad N. Viswanadhan¶, Attila Toth||, Larry V. Pearce||, Todd W. Vanderah**, Frank Porreca**, Peter M. Blumberg||, Jack Lile, Yax Sun¶, Ken Wild, Jean-Claude Louis, and James J. S. Treanor

From the Departments of Neuroscience and ^¶Molecular Structure, Amgen Inc., Thousand Oaks, California 91320-1799, the ^||Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, NIH, Bethesda, Maryland 20892, and the ^**Department of Pharmacology, the University of Arizona College of Medicine, Tucson, Arizona 85724-5017

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 [³H]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 (Met⁵⁴⁷ and Thr⁵⁵⁰) in transmembrane regions 3 and 4 (TM3/4) of rat and human TRPV1 that confer vanilloid sensitivity, [³H]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.

Received for publication, November 18, 2003 , and in revised form, February 27, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY487342.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Neuroscience, Amgen Inc., MS 29-2-B, One Amgen Center Dr., Thousand Oaks, CA 91320-1799. Tel.: 805-447-0607; Fax: 805-480-1347; E-mail: ngavva{at}amgen.com.

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