Pharmacology of Vanilloid Transient Receptor Potential Cation Channels

Joris Vriens; Giovanni Appendino; Bernd Nilius

doi:10.1124/mol.109.055624

Abstract

Depending on their primary structure, the 28 mammalian transient receptor potential (TRP) cation channels identified so far can be sorted into 6 subfamilies: TRPC (“Canonical”), TRPV (“Vanilloid”), TRPM (“Melastatin”), TRPP (“Polycystin”), TRPML (“Mucolipin”), and TRPA (“Ankyrin”). The TRPV subfamily (vanilloid receptors) comprises channels critically involved in nociception and thermosensing (TRPV1, TRPV2, TRPV3, and TRPV4), whereas TRPV5 and TRPV6 are involved in renal Ca²⁺ absorption/reabsorption. Apart from TRPV1, the pharmacology of these channels is still insufficiently known. Furthermore, only few small-molecule ligands for non-TRPV1 vanilloid receptors have been identified, and little is known of their endogenous ligands, resulting in a substantial “orphan” state for these channels. In this review, we summarize the pharmacological properties of members of the TRPV subfamily, highlighting the critical issues and challenges facing their “deorphanization” and clinical exploitation.

Footnotes

↵1 The structures of compounds LY2934001, HC-01403, GRC 15133, GRC 17173, and RN-9893 have not been disclosed in the public literature and are found only in patent applications currently under examination and not available for inspection. Therefore, unless and until these structures are made public, it is impossible to independently verify or replicate results associated with those compounds.
This work was supported by the Belgian Federal Government; the Flemish Government; and the Onderzoeksraad Katholieke Universiteit Leuven [Grant GOA 2004/07, Fonds voor Wetenschappelijk OnderzoekG. 0136.00; Fonds voor Wetenschappelijk OnderzoekG. 0172.03, Interuniversity Poles of Attraction Program, Prime Ministers OfficeIUAP Nr.3P4/23, and ExcellentiefinancieringEF/95/010].
ABBREVIATIONS: TRP, transient receptor potential; TM, transmembrane domain; TRPV, transient receptor potential receptor vanilloid; AEA, N-arachidonylethanolamine; NADA, N-arachidonoyldopamine; RTX, resiniferatoxin; TG, trigeminal; DRG, dorsal root ganglia; 2-APB, 2-aminoethoxydiphenyl borate; RR, ruthenium red; OLEA, N-oleoylethanolamine; HPETE, hydroperoxyeicosatetraenoic acid; HEK, human embryonic kidney; IP₃, inositol triphosphate; CGRP, calcitonin gene-related peptide; PIP2, phosphatidylinositol biphosphate; PKA, protein kinase A; PKC, protein kinase C; 5HT, 5-hydroytryptamine; BCTC, N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide; TBA, tetrabutylammonium; PI(3), phosphatidylinositol 3; PAR2, protease-activated receptor 2; QX-314, 2-((2,6-dimethylphenyl)amino)-N,N,N-triethyl-2-oxoethanaminium; DPTHF, 2,2-diphenyltetrahydrofuran; DPBA, diphenylboronic anhydride; PLA2, phospholipase A2; EET, epoxyeicosatrienoic acid; BAA, bisandrographolide A; PLC, phospholipase C; OAG, 1-oleoyl-acetyl-sn-glycerol; PTH, parathyroid hormone; DD161515, N-[2-(2-(N-methylpyrrolidinyl)ethyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide; U73122, 1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione; RN-1734, 1-alkoxycarbonylalkylidenetriphenylarsoranes.
- Received February 16, 2009.
- Accepted March 17, 2009.