TRPV

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Transient receptor potential (TRP) ion channel
Identifiers
Symbol TRP
Pfam PF06011
InterPro IPR010308

Transient receptor potential channels (TRP channels) are a large group of ion channels, comprising six protein families, located mostly on the plasma membrane of numerous human and animal cell types, and in some fungi.[1] TRP channels were initially discovered in the trp mutant strain of the fruit fly Drosophila [2] which displayed transient elevation of potential in response to light stimuli and were so named "transient receptor potential" channels.[3] The name now refers only to a family of proteins with similar structure and function, not to the mechanism of their activation. Later, TRP channels were found in vertebrates where they are ubiquitously expressed in many cell types and tissues. There are about 28 TRP channels that share some structural similarity to each other.[4] These are grouped into two broad groups: group 1 includes, TRPC ( "C" for canonical), TRPV ("V" for vanilloid), TRPM ("M" for melastatin), TRPN and TRPA. In group 2 there are TRPP ("P" for polycystic) and TRPML ("ML" for mucolipin). TRPC, ion channels are relatively non-selectively permeable to cations, including sodium, calcium and magnesium, but all TRPVs, TRPM3, TRPM6 and TRPM7 are highly calcium selective.

Sub-families[edit]

They are encoded by at least 100 channel subunit genes divided into seven sub-families:

Structure[edit]

Most TRP channels are composed of 6 membrane-spanning helices with intracellular N- and C-termini. Mammalian TRP channels are activated and regulated by a wide variety of stimuli including many post-transcriptional mechanisms like phosphorylation, G-protein receptor coupling, ligand-gating, and ubiquitination. The receptors are found in almost all cell types and largely localized in the cell membrane, modulating ion entry.

Function[edit]

TRP channels modulate ion entry driving forces and Ca2+ and Mg2+ transport machinery in the plasma membrane, where most of them are locate. TRPs have important interactions with other proteins and often form signaling complexes, the exact pathways of which are unknown.[1] TRPMs function as intracellular calcium release channels and thus serve an important role in organelle regulation.[1] Importantly, many of these channels mediate a variety of sensations like the sensations of pain, hotness, warmth or coldness, different kinds of tastes, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and are used in animals to sense hot or cold. TRPs act as sensors of osmotic pressure, volume, stretch, and vibration. TRPs have been seen to have complex multidimensional roles in sensory signaling.Intracellular. Many TRPs function as intracellular calicum release channels.

Pain and Temperature Sensation[edit]

Trp ion channels convert energy into action potentials in somatosensory nociceptors.[5] Thermo-TRP channels have a C-terminal domain that is responsible for thermosensation and have a specific interchangeable region that allows them to sense temperature stimuli that is tied to ligand regulatory processes.[6] There are 6 different Thermo-TRP channels and each plays a different role. For instance, TRPM8 relates to mechanisms of sensing cold, TRPV1 contributes to heat and inflammation sensations, and TRPA1 facilitates many signaling pathways like sensory transduction, nociception, inflammation and oxidative stress.[5]

Taste[edit]

The TRP channels play a significant role in taste with channels responding to different tastes. TRPA responds to mustard oil, wasabi, and cinnamin, TRPA1 and TRPV responds to garlic (allicin), TRPV responds to to chilli pepper (capsaicin), TRPA responds to wasabi (allyl isothiocyanate) and mustard oil; Trpm is activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules (THC, CBD and CBN) found in marijuana.

TRP-like channels in insect vision[edit]

Figure 1. Light-activated TRPL channels in Periplaneta americana photoreceptors. A, a typical current through TRPL channels was evoked by a 4-s pulse of bright light (horizontal bar). B, a photoreceptor membrane voltage response to the light-induced activation of TRPL channels, data from the same cell are shown

The trp mutant fruit flies, that lack a functional copy of trp gene, are characterized by a transient response to light unlike wild-type flies that demonstrate a sustained photoreceptor cell activity in response to light.[7] A distantly related isoform of TRP channel, TRP-like channel (TRPL) was later identified in Drosophila photoreceptors, where it is expressed at approximately 10 to 20-fold lower levels than TRP protein. A mutant fly, trpl, was subsequently isolated. Apart from structural differences, the TRP and TRPL channels differ in cation permeability and pharmacological properties.

TRP/TRPL channels are solely responsible for depolarization of insect photoreceptor plasma membrane in response to light. When these channels open, they allow sodium and calcium to enter the cell down the concentration gradient, which depolarizes the membrane. Variations in light intensity affect the total number of open TRP/TRPL channels, and, therefore the degree of membrane [depolarization]. These graded voltage responses propagate to [photoreceptor] synapses with second-order retinal neurons and further to the brain.

Importantly, the mechanism of insect photoreception is dramatically different from that in mammals. Excitation of rhodopsin in mammalian photoreceptors leads to the hyperpolarization of the receptor membrane but not to depolarization like in the insect eye. In Drosophila and presumably other insects, a phospholipase C (PLC)-mediated signaling cascade links photoexcitation of rhodopsin to the opening of the TRP/TRPL channels. Although numerous activators of these channels such as phosphatidylinositol-4,5-bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) were known for years, a key factor mediating chemical coupling between PLC and TRP/TRPL channels remained a mystery until recently. It was found that breakdown of a lipid product of PLC cascade, diacylglycerol (DAG), by the enzyme Diacylglycerol lipase, generates PUFAs that can activate TRP channels thus initiating membrane depolarization in response to light.[8] This mechanism of TRP channel activation may be well preserved among other cell types where these channels perform various functions.

Clinical Significance[edit]

Mutations in TRPs have been linked to neurodegenerative disorders, skeletal dysplasia, kidney disorders,[1] and may play an important role in cancer. TRPs may make important therapeutic targets. There is significant clinical significance to TRPV1, TRPV2, TRPV3 and TRPM8’s role as thermoreceptors, and TRPV4 and TRPA1’s role as mechanoreceptors; reduction of chronic pain may be possible by targeting ion channels involved in thermal, chemical, and mechanical sensation to reduce their sensitivity to stimuli.[9] For instance the use of TRPV1 agonists would potentially inhibit nociception at TRPV1, particularly in pancreatic tissue where TRPV1 is highly expressed.[10] The TRPV1 agonist capsaicin, found in chili peppers, has been indicated to relieve neuropathic pain.[1] TRPV1 agonists inhibit nociception at at TRPV1

Role in Cancer[edit]

Altered expression of TRP proteins often leads to tumorigenesis, clearly seen in TRPM1, TRPV6, TRPM1.[10] Particularly high levels of TRPM1 and TRPV6 in prostate cancer and of TRPM1 in melanomas have been noted. Such observations could be helpful in following cancer progression and could lead to the development of drugs over activating ion channels, leading to apoptosis and necrosis. Much research remains to be done as to whether TRP channel mutations lead to cancer progression or whether they are associated mutations.

History of Drosophila TRP channels[edit]

The original TRP mutant in Drosophila was first described by Cosens and Manning in 1969 as a "a mutant strain of D. melanogaster which, though behaving phototactically positive in a T-maze under low ambient light, is visually impaired and behaves as though blind". It also showed an abnormal electroretinogram (ERG) response to light[11] and it was investigated subsequently by Baruch Minke, a post-doc in the group of William Pak, and named TRP according to its behavior in the ERG.[7] The identity of the mutated protein was unknown until it was cloned by Craig Montell, a post doctoral researcher in Gerald Rubin's research group, in 1989, who noted its predicted structural relationship to channels known at the time [12] and Roger Hardie and Baruch Minke who provided evidence in 1992 that it was an ion channel that opened in response to light stimulation.[13] The TRPL channel was cloned and characterized in 1992 by the research group of Leonard Kelly.[14]

References[edit]

  1. ^ a b c d e Winston, K. R.; Lutz, W (1988). "Linear accelerator as a neurosurgical tool for stereotactic radiosurgery". Neurosurgery 22 (3): 454–64. PMID 3129667.  edit
  2. ^ Cosens, D. J.; Manning, A (1969). "Abnormal electroretinogram from a Drosophila mutant". Nature 224 (5216): 285–7. PMID 5344615.  edit
  3. ^ Montell, C; Rubin, G. M. (1989). "Molecular characterization of the Drosophila trp locus: A putative integral membrane protein required for phototransduction". Neuron 2 (4): 1313–23. PMID 2516726.  edit
  4. ^ Islam MS, ed. (January 2011). Transient Receptor Potential Channels. Advances in Experimental Medicine and Biology 704. Berlin: Springer. p. 700. ISBN 978-94-007-0264-6. 
  5. ^ a b Eccles, R (1989). "Nasal physiology and disease with reference to asthma". Agents and actions. Supplements 28: 249–61. PMID 2683630.  edit
  6. ^ Brauchi, S; Orta, G; Salazar, M; Rosenmann, E; Latorre, R (2006). "A hot-sensing cold receptor: C-terminal domain determines thermosensation in transient receptor potential channels". Journal of Neuroscience 26 (18): 4835–40. doi:10.1523/JNEUROSCI.5080-05.2006. PMID 16672657.  edit
  7. ^ a b Cosens DJ, Manning A; Manning (1969). "Abnormal electroretinogram from a Drosophila mutant". Nature 224 (5216): 285–287. Bibcode:1969Natur.224..285C. doi:10.1038/224285a0. PMID 5344615. 
  8. ^ Leung HT, Tseng-Crank J, Kim E, Mahapatra C, Shino S, Zhou Y, An L, Doerge RW, Pak WL.; Tseng-Crank; Kim; Mahapatra; Shino; Zhou; An; Doerge; Pak (2008). "DAG lipase activity is necessary for TRP channel regulation in Drosophila photoreceptors". Neuron 6 (58): 884–896. doi:10.1016/j.neuron.2008.05.001. PMC 2459341. PMID 18579079. 
  9. ^ Levine, J. D.; Alessandri-Haber, N (2007). "TRP channels: Targets for the relief of pain". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1772 (8): 989–1003. doi:10.1016/j.bbadis.2007.01.008. PMID 17321113.  edit
  10. ^ a b Prevarskaya, N; Zhang, L; Barritt, G (2007). "TRP channels in cancer". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1772 (8): 937–46. doi:10.1016/j.bbadis.2007.05.006. PMID 17616360.  edit
  11. ^ Cosens DJ, Manning A; Manning (October 1969). "Abnormal electroretinogram from a Drosophila mutant". Nature 224 (5216): 285–287. Bibcode:1969Natur.224..285C. doi:10.1038/224285a0. PMID 5344615. 
  12. ^ Montell C, Rubin GM; Rubin (April 1989). "Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction". Neuron 2 (4): 1313–23. doi:10.1016/0896-6273(89)90069-X. PMID 2516726. 
  13. ^ Hardie RC, Minke B; Minke (April 1992). "The trp gene is essential for a light-activated Ca2+ channel in Drosophila photoreceptors". Neuron 8 (4): 643–51. doi:10.1016/0896-6273(92)90086-S. PMID 1314617. 
  14. ^ Phillips AM, Bull A, Kelly LE; Bull; Kelly (April 1992). "Identification of a Drosophila gene encoding a calmodulin-binding protein with homology to the trp phototransduction gene". Neuron 8 (4): 631–42. doi:10.1016/0896-6273(92)90085-R. PMID 1314616. 

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