TRPV1

transient receptor potential cation channel, subfamily V, member 1

Homology model of the TRPV1 ion channel tetramer (where the monomers are individually colored cyan, green, blue, and magenta respective) imbedded in a cartoon representation of a lipid bilayer. PIP2 signaling ligands are represented by space-filling models (carbon = white, oxygen = red, phosphorous = orange).[1]
Identifiers
Symbols TRPV1; DKFZp434K0220; VR1
External IDs OMIM: 602076 MGI: 1341787 HomoloGene: 12920 IUPHAR: TRPV1 GeneCards: TRPV1 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 7442 193034
Ensembl ENSG00000196689 ENSMUSG00000005952
UniProt Q8NER1 Q3V318
RefSeq (mRNA) NM_018727 NM_001001445
RefSeq (protein) NP_061197 NP_001001445
Location (UCSC) Chr 17:
3.42 – 3.45 Mb		 Chr 11:
73.05 – 73.08 Mb
PubMed search [1] [2]

The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins which in turn are a sub family of the transient receptor potential protein group.[2][3] This protein is a member of the TRPV group of transient receptor potential family of ion channels.[4]

The function of TRPV1 is detection and regulation of body temperature. Additionally, TRPV1 provides sensation of scalding heat and pain (nociception).

Contents

Function

TRPV1 is a nonselective cation channel that may be activated by a wide variety of exogenous and endogenous physical and chemical stimuli. The best-known activators of TRPV1 are heat greater than 43°C, capsaicin, the pungent compound in hot chili peppers, and allyl isothiocyanate, the pungent compound in mustard and wasabi.[5] The activation of TRPV1 leads to a painful, burning sensation. Its endogenous activators include: low pH (acidic conditions), the endocannabinoid anandamide, N-arachidonoyl-dopamine. TRPV1 receptors are found mainly in the nociceptive neurons of the peripheral nervous system, but they have also been described in many other tissues, including the central nervous system. TRPV1 is involved in the transmission and modulation of pain (nociception), as well as the integration of diverse painful stimuli.[6][7]

Sensitization

The sensitivity of TRPV1 to noxious stimuli, such as high temperatures is not static. Upon tissue damage and the consequent inflammation, a number of inflammatory mediators, such as various prostaglandins and bradykinin, are released. These agents increase the sensitivity of nociceptors to noxious stimuli. This manifests as an increased sensitivity to painful stimuli (hyperalgesia) or pain sensation in response to non-painful stimuli allodynia. Most sensitizing pro-inflammatory agents activate the phospholipase C pathway. Phosphorylation of TRPV1 by protein kinase C have been shown to play a role in sensitization of TRPV1.

Desensitization

Upon prolonged exposure to capsaicin, TRPV1 activity decreases, a phenomenon called desensitization. Extracellular calcium ions are required for this phenomenon, thus influx of calcium and the consequential increase of intracellular calcium mediate this effect. Various signaling pathways such as calmodulin and calcineurin, and the decrease of PIP2, have been implicated in desensitization of TRPV1. Desensitization of TRPV1 is thought to underlie the paradoxical analgesic effect of capsaicin.

Clinical significance

Peripheral nervous system

Treatment of pain is an unmet medical need costing billions of dollars every year. As a result of its involvement in nociception, TRPV1 has been a prime target for the development of novel pain reducers (analgesics). Two major strategies have been used:

Antagonists

Antagonists block TRPV1 activity, thus reducing pain. These agents could be useful when applied systemically.[8] Numerous TRPV1 antagonists have been developed by pharmaceutical companies. TRPV1 antagonists have shown efficacy in reducing nociception from inflammatory and neuropathic pain models in rats.[9] This provides evidence that TRPV1 is the capsaicin's sole receptor.[10] In humans, drugs acting at TRPV1 receptors could be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, or amputation, as well as pain associated with the inflammatory response of damaged tissue, such as in osteoarthritis.[11]

The major roadblock for the usefulness of these drugs is their effect on body temperature (hyperthermia). The role of TRPV1 in the regulation of body temperature has emerged in the last few years. Based on a number of TRPV-selective antagonists' causing an increase in body temperature (hyperthermia), it was proposed that TRPV1 is tonically active in vivo and regulates body temperature[12] by telling the body to "cool itself down". Without these signals, the body overheats. Similarly, this explains the propensity of capsaicin (a TRPV1 agonist) to cause sweating (i.e.: a signal to reduce body temperature). In a recent report, it was found that tonically active TRPV1 channels are present in the viscera and keep an ongoing suppressive effect on body temperature.[13] Recently, it was proposed that predominant function of TRPV1 is body temperature maintenance [14] Experiments have shown that TRPV1 blockade increases body temperature in multiple species, including rodents and humans, suggesting that TRPV1 is involved in body temperature maintenance.[12] Recently, AMG 517, a highly selective TRPV1 antagonist was dropped out of clinical trials due to the undesirable level of hyperthermia.[15] A second molecule, SB-705498 was also evaluated in the clinic but its effect on body temperature was not reported.[16] Recently, it was disclosed that clinical trials of two more TRPV1 antagonists, GRC 6211 and NGD 8243 have been stopped. Post translational modification of TRPV1 protein by its phosphorylation is critical for its functionality. Recent reports published from NIH suggest that Cdk5 mediated phosphorylation of TRPV1 is required for its ligand-induced channel opening.[17]

Agonists

Agonists such as capsaicin and resiniferatoxin activate TRPV1, and, upon prolonged application TRPV1 activity, would decrease (desensitization), leading to alleviation of pain. Agonists can be applied locally to the painful area as through a patch or an ointment. Numerous capsaicin-containing creams are available over the counter, containing low concentrations of capsaicin (0.025 - 0.075%). It is debated whether these preparations actually lead to TRPV1 desensitization, it is possible that they act via counter-irritation. Novel preparations containing higher capsaicin concentration (up to 10%) are under clinical trials.[18] 8% capsaicin patches have recently become available for clinical use, with supporting evidence demonstrating that a 30 minute treatment can provide up to 3 months analgesia by causing regression of TRPV1 containing neurones in the skin.[19]

Central nervous system

TRPV1 is also expressed at high levels in the central nervous system and has been proposed as a target for treatment not only of pain but also for other conditions such as anxiety.[20] Furthermore TRPV1 appears to mediate long term depression (LTD) in the hippocampus.[21] LTD has been linked to a decrease in the ability to make new memories, unlike its opposite long term potentiation (LTP), which aids in memory formation. A dynamic pattern of LTD and LTP occurring at many synapses provides a code for memory formation. Long-term depression and subsequent pruning of synapses with reduced activity is an important aspect of memory formation. In rat brain slices, activation of TRPV1 with heat or capsaicin induced LTD while capsazepine blocked capsaicin's ability to induce LTD.[21] In the brain stem (solitary tract nucleus), TRPV1 controls the asynchronous and spontaneous release of glutamate from unmyelinated cranial visceral afferents - release processes that are active at normal temperatures and hence quite distinct from TRPV1 responses in painful heat.[22] Hence there may be therapeutic potential in modulating TRPV1 in the central nervous system, perhaps as a treatment for epilepsy (TRPV1 is already a target in the peripheral nervous system for pain relief).

Discovery

The DRG neurons of mammals were known to express a heat-sensitive ion channel which could be activated by capsaicin.[23] The research group of David Julius therefore created a cDNA library of genes expressed in dorsal root ganglion neurons, expressed the clones in HEK 293 cells and looked for cells which respond to capsaicin with calcium influx (which HEK-293 normally not do). After several rounds of screening and diving the library a single clone encoding the TRPV1 channel was finally identified in 1997. It was the first TRPV channel to be identified.[2]

Interactions

TRPV1 has been shown to interact with Calmodulin 1,[24] SYT9[25] and SNAPAP.[25]

Hacking

One example of modularity and hacking opportunity is the heat activation domain. TRPV proteins are activated by heat on the C-termimus, while TRPM proteins are activated by cold temperatures (<23-28°C) in the same location. Exchanging the C-terminals for each other, could then activate these proteins at different than normal temperatures.[26] Chemical genetics has also been used to introduce TRPV1 into cells that do not normally express it. When capsaicin is added, those cells are then activated by the influx of calcium. This system is not as fast as other controls, such as optogenetics, but remains an important mechanism of spatial and temporal control.[27] This method of control can be applied to a variety of systems and cells, and will most likely be expanded and improved in the near future.

See also

References

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Further reading

External links