TRPV

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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]

TRPV (Transient Receptor Potential Vanilloid) is a family of transient receptor potential (TRP) ion channels.[2][3] These channels are selective for calcium and magnesium over sodium ions. Like other members of the TRP superfamily, TRPV channels can be activated through seemingly disparate mechanisms.[4] In vertebrates, several members of the family are sensitive to elevated temperature, making them thermoTRPs.[5]

The first member of this family that was isolated, TRPV1, is also sensitive to capsaicin, the pungent ingredient in "hot" chili peppers and accordingly TRPV1 is also sometimes referred to as the capsaicin or vanilloid receptor.[6]

The number of TRPV channel variants differs between species. Worms have 5, flies only 2, mice and humans 6 distinct receptors. The TRPV receptors can also form heteromers that exhibit unique conductance and gating properties, further increasing their functional diversity.[3]

Discovery[edit]

The first mammalian TRPV channel, named VR1 at the time, was cloned from a rat and characterized in the laboratory of David Julius at the UCSF, and the results were published in the journal Nature in 1997.[6][7] The homolog gene of TRPV1 in C. elegans was independently discovered in the same year, and its protein OSM-9 characterized by another research group at UCSF led by Cornelia Bargmann.[8] These discoveries defined the first typical family beyond the classical TRPC channels.[9] The 2nd mammalian TRPV channel was identified in 1999, also by Julius' group.[10] By 2002, Bargmann's group had identified all currently known TRPV genes in C. elegans and D. melanogaster.[11] In the same year three research groups simultaneously identified TRPV3, and characterized its thermal sensitivity.[12][13][14]

Structure[edit]

Functional TRPV ion channels are tetrameric in structure and are either homo-tetrameric (four identical subunits) or hetero-tetrameric (a total of four subunits selected from two or more types of subunits). The four subunits are symmetrically arranged around the ion conduction pore. Although the extent of heteromerization has been the subject of some debate, the most recent research in this area suggest that all four thermosensitive TRPVs (1-4) can form heteromers with each other. This result is in line with the general observation that TRP coassembly tends to occur between subunits with high sequence similarities. How TRP subunits recognize and interact with each other is still poorly understood.[3][15]

The TRPV channel monomeric subunit components each contain six transmembrane (TM) domains (designated S1–S6) with a pore domain between the fifth (S5) and sixth (S6) segments.[16] TRPV subunits contain three to five N-terminal ankyrin repeats.[17]

Activation and functions[edit]

Vertebrates[edit]

TRPV channels can be activated through a variety of mechanisms. TRPV1 to TRPV4 can act as thermometers on a molecular level. Interestingly, each of these channels has a different thermal threshold for activation: TRPV2 is activated at 52 °C, TRPV1 at 43 °C, TRPV3 at 33 °C, and TRPV4 below 33 °C when expressed in transfected permanent cell lines (HEK293 and CHO cells) and in frog oocytes. This has not been proven in sensory neurons where for example no correlation between TRPV2 and heat sensitivity could be shown.[4][5][18] TRPV1 is essential for inflammatory thermal hyperalgesia.[19][20] In addition to noxious heat, TRPV1 is activated by acidic pH, the inflammatory vanilloid compound capsaicin, pungent substances present in black pepper (piperine) and garlic (allicin), the topical analgesic camphor, and the endocannabinoids anandamide and N-arachidonoyl-dopamine.[4][21] The other TRPV family members are insensitive to vanilloid compounds.[4] TRPV3 is activated by essential oils from clove (eugenol), thyme (thymol) and oregano (carvacrol).[22] TRPV3 is highly expressed in the nose, which may explain why the odors of these plants are associated with a sensation of warmth.[5] Like TRPV1, TRPV3 is also activated by camphor.[23] TRPV4 can be activated by cell swelling caused by 5',6'-ep-oxyeicosatrienoic acid.[24] As of 2008, a knockout mouse model for TRPV2 is not available, making it difficult to assess additional roles of this channel.[3]

The group 2 TRPV5 and TRPV6 are calcium entry channels responsible for calcium absorption in the kidney and intestine respectively. They were originally named ECaC[25] and CAT1.[26] and expression is regulated by the vitamin D receptor (VDR) through the active metabolite calcitriol.[27]

The table below summarizes the functions and properties of the individual TRPV channel family members:[2][4]

group channel function tissue distribution Ca2+/Na+
selectivity
heteromeric associated subunits other associated proteins
1 TRPV1 vanilloid (capsaicin) receptor and noxious thermosensor (43 °C) CNS and PNS 9:1 TRPV2, TRPV3 calmodulin, PI3 kinase
TRPV2 osmo- and noxious heat thermosensor (52 °C) CNS, spleen and lung 3:1 TRPV1
TRPV3 warmth sensor channel (33-39 °C) Skin, CNS and PNS 12:1 TRPV1
TRPV4 osmo- and warmth sensor channel (27-34 °C) CNS and internal organs 6:1 aquaporin 5, calmodulin, pacsin 3
2 TRPV5 calcium-selective TRP channel intestine, kidney, placenta 100:1 TRPV6 annexin II / S100A10, calmodulin
TRPV6 calcium-selective TRP channel kidney, intestine 130:1 TRPV5 annexin II / S100A10, calmodulin

Nematodes[edit]

In C. elegans, the OSM-9 protein is localized to the AWA sensory cilia. The olfactory function of this protein is confirmed by the fact that osm-9 mutants have a near-complete defect in the functions of ciliated sensory neurons, called ASH neurons, that act as polymodal nociceptors. These neurons mediate behavioral avoidance of high osmolarity, mechanical stimuli, noxious odors, heavy metals, bitter substances like quinine, and acid pH.[9] Wild C. elegans is insensitive to capsaicin, but if it is genetically modified to express TRPV1 instead of osm-9, then its ASH nociceptor neurons make it avoid capsaicin.[11]

Flies[edit]

In D. melanogaster, the two TRPV proteins Nan (Nanchung) and Iav (Inactive) play a key role in the auditory chordotonal neurons in Johnston's organ. Mutations in either of these genes render the fly deaf. A possible explanation for this interdependency is that the two proteins form heteromers in vivo and depend on each other for protein stability. The most intriguiging finding is that alterations to Iav (but not Nan) alters Drosophila's sensitivity to cocaine.[28]

Genes[edit]

There are six human genes encoding TRPV ion channels divided into two groups based on sequence homology and functional similarity:[29]

In C. elegans there are two groups of genes that encode TRPV channels. One group contains a single gene, osm-9. The second group contains four ocr genes (osm-9/capsaicin receptor related). In D. melanogaster there are only two genes, one related to osm-9, called inactive, and another related to the ocr genes, called nanchung. This observation suggest that the common ancestor of nematodes and files had at least one osm-9-like gene and at least one ocr-like gene.[3][11]

As drug targets[edit]

Four TRPVs (TRPV1, TRPV2, TRPV3, and TRPV4) are expressed in afferent nociceptors, pain sensing neurons, where they act as transducers of thermal and chemical stimuli. Hence antagonists or blockers of these channels may find application for the prevention and treatment of pain.[30] A number of TRPV1 selective blockers are currently in clinical trials for the treatment of various types of pain.[7]

References[edit]

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