Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2012.11
Gene Symbol: TRPV1;
Other names: Vanilloid Receptor 1 (VR1), Capsaicin Receptor
1. General Information
Background and structure
Transient receptor potential vanilloid receptor 1 (TRPV1) is one of 6 members of the subfamily of vanilloid receptors that belongs to the family of transient receptor potential (TRP) channels. TRP channels are an intrinsic part of the mammalian sensory system responding to a broad range of stimuli such as temperature, touch, pain, osmolarity, pheromones, and taste (8). TRPV1, TRPV2, TRPV3 and TRPV4 are all involved in thermoactivation. These channels share a similar structure with 6 putative transmembrane domains, a loop structure between transmembrane regions 5 and 6 believed to be involved in pore formation, ankyrin repeats, and both the N- and C-termini located in the cytoplasm (8, 41).
TRPV1 plays an important role in nociception and was the first of the TRPV family channels to be cloned. TRPV1 was cloned using capsaicin, the pungent component of hot chili pepper, by screening an expression cDNA library of dorsal root ganglia (5). TRPV1 is a non-selective cation channel and can be activated by numerus stimuli such as vanilloids (capsaicin, resiniferatoxin), low pH, elevated temperature (10), endogenous lipoxygenases (leukotriene B4, 12- or 15-HPETE) (24), endogenous anandamide (40) and ethanol (43). In addition, ethanol can potentiate the effects of capsaicin, protons and heat. TRPV1 is broadly distributed. It is highly expressed in dorsal root ganglia, trigeminal ganglia, in small sensory C fibers and some Aδ fibers. It is also detectable in brain, spinal cord, bladder, kidney, liver, spleen, testis, lung and bowel (17).
The cation selective channel is probably made of a tetrameric quaternary structure (25). Modulation of the activity of TRPV1 is under the control of many intracellular signals that act on the N-terminal and C-terminal portions of the monomer including phosphorylation. Binding of pro-inflammatory agents such as prostaglandins to its receptor induces a cascade of events that lead to activation of cAMP-dependent protein kinase that in turn can phosphorylate TRPV1. Histamine can also activate TRPV1 through phosphorylation by protein kinase C (PKC). Activation of TRPV1 contributes to the release of substance P and CGRP from peripheral terminal of neurons (25).
TRPV1 is activated by a number of agonists (see Table 1) although clear identification of endogenous ligands has been elusive. Increased temperature is a well-established pathological activator of TRPV1 under certain conditions. Local acidification can activate TRPV1 and cause pain and inflammation. There is accumulating evidence for endogenous chemical mediators such as anandamide or leukotrienes in TRPV1 activation.
Intracellular Ca2+ is involved in the mechanism of sensitization of TRPV1. Increased intracellular Ca2+ results in activation of phospholypase C (PLC) (35) which hydrolyses the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into 1,4,5-trisphosphate (IP3) and diacylglycerol. In an opposing effect, depletion of PIP2 is responsible for desentization of TRPV1 (35).
Three alternatively spliced TRPV1 mRNAs have been characterized: VR.5’sv (38), TRPV1var (42) and TRPV1β (48). The TRPV1var variant expressed in the kidney encodes the first 248 amino-acids and comprises only one ankyrin domain (42). Another variant called VR.5’sv, expressed in DRG, brain and peripheral blood mononuclear cells is missing most of the N-terminal region and two ankyrin domains (38). Finally, the third alternatively spliced TRPV1 variant known as TRPV1β lacks amino-acids 399 to 408 (before the first transmembrane domain). Interestingly, all these variants can modulate the activity of the canonical TRPV1 protein as demonstrated by coexpression studies of TRPV1 with the variants (38, 42, 48).
The role of TRPV1 in pain sensation has been clearly demonstrated by the advent of TRPV1 knockout mice (4). Knockout mice exhibited impaired thermal sensitivity to pain triggered by heat or capsaicin.
TRPV1 has been implicated in neurogenic inflammation using pharmacological agonists and antagonists in animal models and by genetic approaches comparing severity of insults in wild type or TRPV1-/- (KO) mice. Neurogenic inflammation is characterized by edema, hyperalgesia, vasodilatation and inflammatory cell infiltration caused by nociceptor overstimulation at the site of injury. The role of TRPV1 in a variety of inflammatory diseases affecting multiple organs has been an active area of investigation.
In some models, activation of TRPV1 plays a central role in the inflammatory response. TRPV1 is expressed in C-fibers innervating the respiratory tract as well as in lung epithelial cells and has been implicated in bronchoconstriction, mucus secretion, cough, and airway irritation. TRPV1 appears to mediate inflammatory tracheal hyperreactivity to carbachol in sensitized mice (3) and cough after RTX and ethanol treatment (15) which either directly activate or lower the activation threshold for TRPV1.
TRPV1 is also involved in acute and chronic inflammation in a model of knee joint injury (26). However, low dose of the TRPV1 agonist RTX produced an analgesic effect and less edema in a knee joint inflammation model (29) possibly through receptor desensitization. TRPV1 is also present in the bladder and and is involved acute bladder inflammation (7). In addition, TRPV1 promotes inflammation in colitis in both rats (27) and mice (28).
Under certain circumstances, TRPV1 activation may confer protection against inflammation. Activation of TRPV1 by agonists (RTX or SA13353) reduced the severity of ishemia/reperfusion-induced renal injury in rats (45) and the severity of LPS-induced rheumatoid arthritis in mice (32). Similar observations were made in a murine model of experimental autoimmune encephalomyelitis (EAE). SA13353 or capsaicin inhibited the production of TNF-α and IL-1β (44). TRPV1 also had a protective effect against the onset of sepsis after endotoxin treatment (LPS) (9) and in rat model of sepsis by cecal ligation and puncture (12). As a member of the acid sensing system, TRPV1 participates in the homeostasis of gastric acid secretion through activation of the sensory nerves and release of CGRP (18-20).
Thus depending upon the cellular environment, TRPV1 may reduce the severity of inflammatory insults or accentuates its effects.
2. TRPV1 and the exocrine pancreas
Acute pancreatitis is associated with vasodilation, edema, neutrophil infiltration and acinar cell necrosis. Many of these features are manifestations of neurogenic inflammation and there is accumulating evidence that neural factors contribute to the pathogenesis of the disease (30). Using the TRPV1 agonist capsaicin to denervate neonatal rats, Nathan and al. demonstrated that TRPV1 mediated the neurogenic aspect of acute pancreatitis (34). Antagonists such as capsazepine (23) or desensitization of pancreatic primary sensory neurons with RTX (36) ameliorated the severity of caerulein-induced pancreatitis.
TRPV1 activation of primary sensory nerves causes the release of substance P during the inflammatory insult (33). Substance P is a 11 amino-acids peptide that stimulates plasma extravasation (14) and genetic deletion of its receptor (NK1-R) ameliorates caerulein induced acute pancreatitis (16). In the search for the endogenous ligands for TRPV1, Hwang and co-workers (24) demonstrated that products from lipoxygenases such as 12-S-HPETE, 15-S-HPETE and LTB4 could directly activate TRPV1 (24). Administration of LTB4 through the celiac artery produced pancreatitis-like inflammation (47). Moreover, blockade of TRPV1 with the TRPV1 antagonist capsazepine or inhibition of the 5-lipoxygenase- activating protein (FLAG) by preteatment with MK886 reduced the severity of the pancreatitis induced by LTB4 indicating that LTB4 was an endogenous ligand of TRPV1 and played a role in inducing acute pancreatitis (47).
TRPV1 and pain sensation during pancreatitis
Through retrograde labeling of pancreatic nerves and immunostaining with anti-TRPV1 antibody it has been possible to localize the pancreatic afferents expressing TRPV1 (13). Dorsal root ganglia (T9-T12) had the highest concentration of neurons expressing TRPV1 (65% of the neurons). Some TRPV1 expressing afferents were also detected in the nodose ganglia where 35% of the neurons expressed TRPV1 (13).
TRPV1 mediates pain in acute pancreatitis. Rats subjected to L-arginine-induced pancreatitis exhibited a 2.5 fold increase of c-fos expression in spinal neurons suggesting activation of nociceptive pathways and a 3 fold increase in spontaneous abdominal contractions (an indicator of nociceptive sensation). Administration of the TRPV1 antagonist capsazepine reduced both c-fos expression and abdominal contractions (49).
TRPV1 activity is potentiated by protease-activated receptor 2 (PAR-2) activation (11, 22). Both TRPV1 and PAR-2 are expressed in the same subset of primary afferent neurons (21) . In HEK293 cells co-expressing both TRPV1 and PAR-2, it was demonstrated that PAR-2 could potentiate the activity of TRPV1. Further, it has been demonstrated that PAR-2 activation by the selective agonist SL-NH2 could cause thermal hyperalgesia and mechanical allodynia at a dose that does not produce inflammation (46). Direct infusion of trypsin or PAR-2 agonist in the pancreatic duct of rats induced a nociceptive response as demonstrated by measurement of an electromyographic recording from the acromiotrapezius (21).
TRPV1 mediates hyperalgesia in a TNBS-induced chronic pancreatitis model in the rat (50). A decrease in the response frequency in the Von Frey filament (VFF) test was observed after administration of the TRPV1 antagonist SB-366791 to rats exhibiting chronic pancreatitis after treatment with TNBS. Interestingly, the level of TRPV1 expression and the number of DRG neurons expressing TRPV1 were increased in these rats. TRPV1’s effect on hyperalgesia in the TNBS-induced model is mediated by nerve growth factor (NGF) (51). Anti-NGF treatment to rats with chronic pancreatitis reduced their response to the VFF test. In addition, TRPV1 expression in DRG neurons was also reduced when rats with chronic pancreatitis were subjected to anti-NGF treatment.
Recently, Schwartz and co-authors (39) demonstrated a synergistic effect of TRPV1 and TRPA1 on both pancreatic pain and inflammation in caerulein-induced acute pancreatitis using specific antagonists for TRPV1 and TRPA1. These findings are in agreement with the observation that the cannabinoid agonist, WIN 55,212-2, known to activate TRPA1, attenuated capsaicin-evoked responses (2). Alternatively, TRPV1 can also modulate the TRPA1 response to nociceptive stimuli as exemplified by TRPV1’s prevention of mustard oil-induced TRPA1 internalization (1). The interactions between TRPV1 and TRPA1 also have been demonstrated in electrophysiological responses in CHO cells co-expressing TRPV1/TRPA1 and in trigeminal sensory neurons. Both cell types exhibited characteristics suggesting that TRPV1 modulates TRPA1 responses (37).
Finally, TRPV4, another channel of the TRP family that can be activated by changes in osmotic pressure (31), is also present in pancreatic sensory nerves and also contributes to nociceptive sensation in caerulein-induced acute pancreatitis (6).
In summary, TRPV1 expressed in primary sensory neurons is involved in neurogenic inflammation of the pancreas and in nociceptive sensation.
3. Tools available for the study of TRPV1
a. TRPV1 Antibodies
A large number of anti-TRPV1 antibodies are available commercially. Most are polyclonal antisera raised in rabbit, goat or even guinea pig, but some monoclonal antibodies are available. Antibodies have been used to identify TRPV1 in rat, human, mouse, chicken and/or zebrafish. Below, are listed some available antisera.
- Gp 14100 (Neuromics, Edina, CA). Used in immunohistochemistry (Baiou et al., J Comp Neurol. 2007; 503:334-337).
- Ab63083 (Abcam, Cambridge, MA). Used in immunohistochemistry (Nie et al., Am J Obstet Gynecol 2010; 202: 346. E1-8).
- ACC-030 (Alomone, Jerusalem, Israel). Used in immunohistochemistry, immunoelectronmicroscopy and western blot (Tominaga et al., Neuron 1998; 21: 531-543).
Affinity purified polyclonal antisera
- P-19 antibody (Santa Cruz Biotechnology, CA; catalog number: sc-12498). Used in Western blots (Vos et al., J Neurochem 2006; 99: 1088-102). Used in immunoprecipitation assay (Stanchev et al., Pain 2009; 143: 26-36).
- N-15 and C-15 antibodies (Santa Cruz Biotechnology, CA; catalog number sc-12500 and sc-12503 respectively). Used in Western blot and immunohistofluorescence (Faussone-Pellegrini et al., (Histochem Cell Biol. 2005; 124: 61-68).
- AB 5370 (EMD-Millipore Calbiochem, Billerica, MA). Used for Western blot, immunohistochemistry and immunoelectron microscopy: Tóth et al., (Brain Res Mol Brain Res. 2005; 135: 162-168).
- PC-420 (EMD-Millipore Calbiochem, Billerica, MA). Used in immunohistochemistry (Zhong et al., Dig Dis Sic. 2008; 53: 194-203).
- Y7101-ig (Abcam, Cambridge, MA). Used in immunochemistry (Peng et al., Am J Physiol Renal Physiol. 2008; 295: F1324-1335).
- H00007442-M01 (Novus Biologicals, Littleton, CO). Used in Western blot (El Karim et al., Pain 2011; 152: 2211-2223).
b. cDNA clones
There are three commercial suppliers of TRPV1 cDNA constructs: Genecopoeia (Rockville, MD); OriGene (Rockville, MD) and DNASU plasmid Repository (ASU-Biodesign Institute, Arizona State University, Arizona). These 3 companies offer human and mouse clones. Rat cDNAs are only offered by Genecopoeia and OriGene
c. Genetically modified mice
Mice with genetic deletion of TRPV1 are available from Jackson Laboratories (catalog number B6.129S4-Trpv1tm1Jul/J).
d. Agonists and antagonists
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- Akopian AN, Ruparel NB, Patwardhan A, and Hargreaves KM. Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation. J Neurosci 28: 1064-1075, 2008. PMID 18234885
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- Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D, and Oh U. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci U S A 97: 6155-6160, 2000. PMID 10823958
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- Kimball ES, Wallace NH, Schneider CR, D'Andrea MR, and Hornby PJ. Vanilloid receptor 1 antagonists attenuate disease severity in dextran sulphate sodium-induced colitis in mice. Neurogastroenterol Motil 16: 811-818, 2004. PMID 15601431
- Kissin EY, Freitas CF, and Kissin I. The effects of intraarticular resiniferatoxin in experimental knee-joint arthritis. Anesth Analg 101: 1433-1439, 2005. PMID 16244007
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- Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, and Heller S. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103: 525-535, 2000. PMID 11081638
- Murai M, Tsuji F, Nose M, Seki I, Oki K, Setoguchi C, Suhara H, Sasano M, and Aono H. SA13353 (1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea) inhibits TNF-alpha production through the activation of capsaicin-sensitive afferent neurons mediated via transient receptor potential vanilloid 1 in vivo. Eur J Pharmacol 588: 309-315, 2008. PMID 18508045
- Nathan JD, Patel AA, McVey DC, Thomas JE, Prpic V, Vigna SR, and Liddle RA. Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis. Am J Physiol Gastrointest Liver Physiol 281: G1322-1328, 2001. PMID 11668042
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- Rohacs T, Thyagarajan B, and Lukacs V. Phospholipase C mediated modulation of TRPV1 channels. Mol Neurobiol 37: 153-163, 2008. PMID 18528787
- Romac JM, McCall SJ, Humphrey JE, Heo J, and Liddle RA. Pharmacologic disruption of TRPV1-expressing primary sensory neurons but not genetic deletion of TRPV1 protects mice against pancreatitis. Pancreas 36: 394-401, 2008. PMID 18437086
- Salas MM, Hargreaves KM, and Akopian AN. TRPA1-mediated responses in trigeminal sensory neurons: interaction between TRPA1 and TRPV1. Eur J Neurosci 29: 1568-1578, 2009. PMID 19419422
- Schumacher MA, Moff I, Sudanagunta SP, and Levine JD. Molecular cloning of an N-terminal splice variant of the capsaicin receptor. Loss of N-terminal domain suggests functional divergence among capsaicin receptor subtypes. J Biol Chem 275: 2756-2762, 2000. PMID 10644739
- Schwartz ES, Christianson JA, Chen X, La JH, Davis BM, Albers KM, and Gebhart GF. Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation. Gastroenterology 140: 1283-1291 e1281-1282, 2011. PMID 21185837
- Smart D, Gunthorpe MJ, Jerman JC, Nasir S, Gray J, Muir AI, Chambers JK, Randall AD, and Davis JB. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol 129: 227-230, 2000. PMID 10694225
- Szallasi A, Cortright DN, Blum CA, and Eid SR. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 6: 357-372, 2007. PMID 17464295
- Tian W, Fu Y, Wang DH, and Cohen DM. Regulation of TRPV1 by a novel renally expressed rat TRPV1 splice variant. Am J Physiol Renal Physiol 290: F117-126, 2006. PMID 16091583
- Trevisani M, Smart D, Gunthorpe MJ, Tognetto M, Barbieri M, Campi B, Amadesi S, Gray J, Jerman JC, Brough SJ, Owen D, Smith GD, Randall AD, Harrison S, Bianchi A, Davis JB, and Geppetti P. Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci 5: 546-551, 2002. PMID 11992116
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- Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, Cirino G, Gerard N, Basbaum AI, Andrade-Gordon P, Hollenberg MD, and Wallace JL. Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. Nat Med 7: 821-826, 2001. PMID 11433347
- Vigna SR, Shahid RA, Nathan JD, McVey DC, and Liddle RA. Leukotriene B4 mediates inflammation via TRPV1 in duct obstruction-induced pancreatitis in rats. Pancreas 40: 708-714, 2011. PMID 21602738
- Wang C, Hu HZ, Colton CK, Wood JD, and Zhu MX. An alternative splicing product of the murine trpv1 gene dominant negatively modulates the activity of TRPV1 channels. J Biol Chem 279: 37423-37430, 2004. PMID 15234965
- Wick EC, Hoge SG, Grahn SW, Kim E, Divino LA, Grady EF, Bunnett NW, and Kirkwood KS. Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 290: G959-969, 2006. PMID 16399878
- Xu GY, Winston JH, Shenoy M, Yin H, Pendyala S, and Pasricha PJ. Transient receptor potential vanilloid 1 mediates hyperalgesia and is up-regulated in rats with chronic pancreatitis. Gastroenterology 133: 1282-1292, 2007. PMID 17698068
- Zhu Y, Colak T, Shenoy M, Liu L, Pai R, Li C, Mehta K, and Pasricha PJ. Nerve growth factor modulates TRPV1 expression and function and mediates pain in chronic pancreatitis. Gastroenterology 141: 370-377, 2011. PMID 21473865