1521-0081/66/3/676–814$25.00 http://dx.doi.org/10.1124/pr.113.008268 PHARMACOLOGICAL REVIEWS Pharmacol Rev 66:676–814, July 2014 Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: DAVID R. SIBLEY Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine Bernd Nilius and Arpad Szallasi KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.); and Department of Pathology, Monmouth Medical Center, Long Branch, New Jersey (A.S.) Abstract. ....................................................................................679 I. Transient Receptor Potential Channels: A Brief Introduction . ...............................679 A. Canonical Transient Receptor Potential Subfamily . .....................................682 B. Vanilloid Transient Receptor Potential Subfamily . .....................................686 C. Melastatin Transient Receptor Potential Subfamily . .....................................696 Downloaded from D. Ankyrin Transient Receptor Potential Subfamily .........................................700 E. Mucolipin Transient Receptor Potential Subfamily . .....................................702 F. Polycystic Transient Receptor Potential Subfamily . .....................................703 II. Transient Receptor Potential Channels: Hereditary Diseases (Transient Receptor Potential Channelopathies). ......................................................704 at Open University Library on January 18, 2020 A. Canonical Transient Receptor Potential Channelopathies. ...............................704 B. Vanilloid Transient Receptor Potential Channelopathies. ...............................705 C. Melastatin Transient Receptor Potential Channelopathies . ...............................708 D. Ankyrin Transient Receptor Potential Channelopathies . ...............................710 E. Mucolipin Transient Receptor Potential Channelopathies. ...............................710 F. Polycystic Transient Receptor Potential Channelopathies . ...............................711 III. Transient Receptor Potential Channels: Acquired Diseases ...................................712 A. The Role of Transient Receptor Potential Channels in Nociception, Pain, and Itch . .......713 1. Basic Concepts .......................................................................713 a. Differential transient receptor potential channel expression defines functional sensory neuron subtypes: Implications for drug development. ...................717 b. Disease-related changes in transient receptor potential channel expression. .......718 2. Transient Receptor Potential Channels in Dental Pain . ...............................720 3. Transient Receptor Potential Channels in Visceral Pain...............................722 a. Esophagus and gastrointestinal tract. ..........................................722 b. Genitourinary tract.. ............................................................725 4. Contribution of Transient Receptor Potential Channels to Neuropathic and Cancer Pain . 727 a. Targeting vanilloid transient receptor potential 1 for pain relief: A brief overview of clinical studies. ................................................727 b. Vanilloid transient receptor potential 3. ..........................................733 c. Melastatin transient receptor potential 8. .........................................734 d. Ankyrin transient receptor potential 1. ..........................................735 5. The Contribution of Transient Receptor Potentials to Chemotherapy-Induced Neuropathic Pain . ..................................................................736 6. Transient Receptor Potential Channels in Migraine ...................................738 a. The role of vanilloid transient receptor potential 1 in migraine and cluster headache.. 738 b. Ankyrin transient receptor potential 1 as a candidate sensor for environmental irritants that provoke migraine attacks. .........................740 Address correspondence to: Arpad Szallasi, Department of Pathology, Monmouth Medical Center, 300 Second Avenue, Long Branch, NJ 07740. E-mail: [email protected] dx.doi.org/10.1124/pr.113.008268. 676 TRP Channels as Drug Targets 677 c. Possible Involvement of other transient receptor potential channels in migraine. 740 d. Migraine as a transient receptor potential channelopathy? .........................740 ABBREVIATIONS: 2-APB, 2-aminoethoxydiphenyl borate; 4aPDD, 4a-phorbol 12,13-didecanoate; A-1165442, (R)-1-(7-chloro-2,2-bis(fluoro- methyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea; A-784168, 3,6-dihydro-39-(trifluoromethyl)-N-[4-[(trifluoromethyl)sulfonyl]phenyl]-[1(2H),29- bipyridine]-4-carboxamide; A-795614, 1-(1H-indazol-4-yl)-3-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea; A-889425, 1-(3-methylpyridin-2-yl)- N-(4-(trifluoromethylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide; A-967079, (1E,3E)-1-(4-fluorophenyl)-2-methyl-1-pentene-3-one oxime; A-993610, (S)-1-(3-chloropyridin-2-yl)-3-methyl-N-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide; ABT-102, (R)-(5-tert- butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea; ABT-116, urea, N-((2-(3,3-dimethylbutyl)-4-(trifluoromethyl)phenyl)methyl)-N9-(1-methyl- 1H-indazol-4-yl); ADPKD, autosomal dominant polycystic kidney disease; ADPR, ADP-ribose; AKAP, A-kinase–anchoring protein; ALS-G, Guamanian amyotrophic lateral sclerosis; AM1241, (2-iodo-5-nitrophenyl)-[1-[(1-methylpiperidin-2-yl)methyl]indol-3-yl]methanone; AM404, N-(4- hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide; AMG517, N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide; AMG9678, (R)-1-(4-(trifluoromethyl)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; AMG9810, (2E)-N-(2,3- dihydro-1,4-benzodioxin-6-yl)-3-[4-(1,1-dimethylethyl)phenyl]-2-propenamide;AMI,acutemyocardialinfarction;AMTB,N-(3-aminopropyl)-2-[3- methylphenyl)methoxy]-N-(2-thienylmethyl)benzamide hydrochloride; AP18, 4-(4-chlorophenyl)-3-methyl-3-buten-2-one oxime; Apo, apolipoprotein; ARD, ankyrin repeat domain; AS1928370, (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-car- boxamide; AZD1386, (S)-N-{1-[4-(t-butyl)-phenyl]-ethyl}-2-(6,7-difluorobenzoimidazol-1-yl)acetamide; BAL, bronchoalveolar lavage; BAT, brown adipose tissue; BayK8644, methyl-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate; BCC, basal cell carcinoma; BCTC, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; BD-I, bipolar disorder type I; BDNF, brain-derived neurotrophic factor; BK, bradykinin; BTP2, N-{4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide; CaM, calmodulin; CaMKII, Ca2+/CaM-dependent kinase II; CB1, cannabinoid receptor 1; CCI, chronic constriction injury; CCK, cholecystokinin; CDK, cyclin-dependent kinase; CFA, complete Freund’s adjuvant; CGRP, calcitonin gene-related peptide; CHO, Chinese hamster ovary; CIPN, chemotherapy-induced peripheral neuropathy; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; COX, cyclooxygenase; CRP, C-reactive protein; CSE, cigarette smoke extract; D-3263, 3-(2-amino-ethyl)-1(R)-[(2(S)-isopropyl-5(R)-methyl cyclohexanecarbonyl)]-5-methoxy- 1,3-dihydro-benzoimidazol-2-one hydrochloride; DAG, diacylglycerol; DRG, dorsal root ganglion; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EPSP, excitatory postsynaptic potential; ERK, extracellular signal-regulated kinase; FD, functional dyspepsia; FDA, US Food and Drug Administration; FK506, tacrolimus; FSGS, focal segmental glomerulosclerosis; GBM, glioblastoma multiforme; GERD, gastroesophageal reflux disease; GLP-1, glucagon-like peptide-1; GPCR, G protein–coupled receptor; GRP, gastrin-releasing peptide; GSK1016790A, (N-((1S)-1-{[4- ((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carbox- amide; GSK205, N-(4-(2-(benzyl(methyl)amino)ethyl)phenyl)-5-(pyridine-3-yl)thiazol-2-amine; H2S, hydrogen sulfide; HC-030031, 2-(1,3-dimethyl-2, 6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; HC-067047, 2-methyl-1-[3-(4-morpholinyl)propyl]-5-phenyl-N-[3-(trifluoro- methyl)phenyl]-1H-pyrrole-3-carboxamide; HCAEC, coronary artery endothelial cell of human origin; hIAP, human islet amyloid polypeptide; HMVEC, human microvascular endothelial cell; HPETE, 12-(S)-5-hydroperoxyeicosatetraenoic acid; HSH, hypomagnesemia with secondary hypocalcemia; IBD, inflammatory bowel disease; IGF, insulin-like growth factor; IL, interleukin; IFN, interferon; iNOS, inducible nitric-oxide synthase; IP3,inositol- 1,4,5-triphosphate; IPAH, idiopathic pulmonary arterial hypertension; IPF, idiopathic pulmonary fibrosis; I-RTX, 5-iodoresiniferatoxin; JNJ17203212, 4-[3-(trifluoromethyl)-2-pyridinyl]-N-[5-(trifluoromethyl)-2-pyridinyl]-1-piperazinecarboxamide; JNJ41876666, 3-[7-trifluoromethyl-5-(2-trifluorome- thyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; JYL1421, N-(4-tertbutylbenzyl)-N-[3-fluoro-4-(methylsulfonylamino) benzyl]-thiourea; KIF13B, kinesin-3 family member 13B; LA, linoleic acid; LPS, lipopolysaccharide; LTB4, leukotriene B4; LTD, long-term depression; LTP, long-term potentiation; MCP1, macrophage