TRPC

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TRPC is a family of transient receptor potential cation channels in animals.

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TRPC channels form the subfamily of channels in humans most closely related to drosophila TRP channels. Structurally, members of this family possess a number of similar characteristics, including 3 or 4 ankyrin repeats near the N-terminus and a TRP box motif containing the invariant EWKFAR sequence at the proximal C-terminus. These channels are non-selectively permeable to cations, with a prevalence of calcium over sodium variable among the different members. Many of TRPC channel subunits are able to coassemble. [1] The predominant TRPC channels in the mammalian brain are the TRPC 1,4 and 5 and they are densely expressed in corticolimbic brain regions, like the hippocampus, prefrontal cortex and lateral septum. [2] [3] These 3 channels are activated by the metabotropic glutamate receptor 1 agonist dihydroxyphenylglycine. [2]

In general, TRPC channels can be activated by phospholipase C stimulation, with some members also activated by diacylglycerol. There is at least one report that TRPC1 is also activated by stretching of the membrane and TRPC5 channels are activated by extracellular reduced thioredoxin. [4]

It has long been proposed that TRPC channels underlie the calcium release activated channels observed in many cell types. [5] These channels open due to the depletion of intracellular calcium stores. Two other proteins, stromal interaction molecules (STIMs) and Orais, however, have more recently been implicated in this process. STIM1 and TRPC1 can coassemble, complicating the understanding of this phenomenon. [1]

TRPC6 has been implicated in late onset Alzheimer's disease. [6]

Role in cardiomyopathies

Research on the role of TRPC channels in cardiomyopathies is still in progress. An upregulation of TRPC1, TRPC3, and TRPC6 genes are seen in heart disease states including fibroblast formation and cardiovascular disease. The TRPC channels are suspected of responding to an overload of hormonal and mechanical stimulation in cardiovascular disease, contributing to pathological remodelling of the heart. [7]

TRPC1 channels are activated by receptors coupled to phospholipase C (PLC), mechanical stimulation, and depletion of intracellular calcium stores. TRPC1 channels are found on cardiomyocytes, smooth muscle, and endothelial cells. [7] Upon stimulation of these channels in cardiovascular disease, there is an increase in hypertension and cardiac hypertrophy. [7] TRPC1 channels mediate smooth muscle proliferation in the presence of pathological stimuli which contributes to hypertension. Mice with myocardial hypertrophy exhibit increased expression of TRPC1. The deletion of the TRPC1 gene in these mice resulted in reduced hypertrophy upon stimulation with hypertrophic stimuli, inferring that TRPC1 has a role in the progression of cardiac hypertrophy. [7]

TRPC3 and TRPC6 channels are activated by PLC stimulation and diacylglycerol (DAG) production. [7] Both these TRPC channel types play a role in cardiac hypertrophy and vascular disease like TRPC1. In addition, TRPC3 is upregulated in the atria of patients with atrial fibrillation (AF). [8] TRPC3 regulates angiotensin II-induced cardiac hypertrophy which contributes to the formation of fibroblasts. Accumulation of fibroblasts in the heart can manifest into AF. Experiments blocking TRPC3 show a decrease in fibroblast formation and reduced AF susceptibility. [8]

TRPC1, TRPC3, and TRPC6 channels are all involved in cardiac hypertrophy. The mechanism of how TRPC channels promote cardiac hypertrophy is through activation of the calcineurin pathway and the downstream transcription factor nuclear factor of activated T-cells (NFAT). [9]

Pathological stress or hypertrophic agonists will trigger G-protein coupled receptors (GPCRs) and activates PLC to form DAG and inositol triphosphate (IP3). [9] IP3 promotes the release of internal calcium stores and the influx of calcium via TRPC. When intracellular calcium reaches a threshold, it will activate the calcineurin /NFAT pathway. DAG activates the calcineurin/NFAT pathway directly. [9] NFAT translocate into the nucleus and induce gene transcription of more TRPC genes. This creates a positive feedback loop, leading to a state of hypertrophic gene expression and thus, cardiac growth and remodelling of the heart. [9] TRPC channel's involvement in well studied signaling pathways and significance in gene impact on human diseases make it a potential target for drug therapy. [10] TRPC has been shown to potentiate inhibition in the olfactory bulb circuit, providing a mechanism for improving olfactory abilities. [11]

Genes

Related Research Articles

<span class="mw-page-title-main">Cardiac muscle</span> Muscular tissue of heart in vertebrates

Cardiac muscle is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of the heart. The cardiac muscle (myocardium) forms a thick middle layer between the outer layer of the heart wall and the inner layer, with blood supplied via the coronary circulation. It is composed of individual cardiac muscle cells joined by intercalated discs, and encased by collagen fibers and other substances that form the extracellular matrix.

<span class="mw-page-title-main">Calcineurin</span> Class of enzymes

Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase. It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of the T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which include ciclosporin, voclosporin, pimecrolimus and tacrolimus.

Transient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC, TRPV, TRPVL, TRPM, TRPS, TRPN, and TRPA. Group 2 consists of TRPP and TRPML. Other less-well categorized TRP channels exist, including yeast channels and a number of Group 1 and Group 2 channels present in non-animals. Many of these channels mediate a variety of sensations such as pain, temperature, different kinds of taste, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold. Some TRP channels are activated by molecules found in spices like garlic (allicin), chili pepper (capsaicin), wasabi ; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis or stevia. Some act as sensors of osmotic pressure, volume, stretch, and vibration. Most of the channels are activated or inhibited by signaling lipids and contribute to a family of lipid-gated ion channels.

<span class="mw-page-title-main">TRPV6</span> Protein-coding gene in the species Homo sapiens

TRPV6 is a membrane calcium (Ca2+) channel protein which is particularly involved in the first step in Ca2+absorption in the intestine.

Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells but has since been found to play an important role in regulating many more body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

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 that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. Fatty acid metabolites with affinity for this receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA). The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). In primary afferent sensory neurons, it cooperates with TRPA1 to mediate the detection of noxious environmental stimuli.

TRPM is a family of transient receptor potential ion channels (M standing for wikt:melastatin). Functional TRPM channels are believed to form tetramers. The TRPM family consists of eight different channels, TRPM1–TRPM8.

<span class="mw-page-title-main">TRPC6</span> Protein and coding gene in humans

Transient receptor potential cation channel, subfamily C, member 6 or Transient receptor potential canonical 6, also known as TRPC6, is a protein encoded in the human by the TRPC6 gene. TRPC6 is a transient receptor potential channel of the classical TRPC subfamily.

<span class="mw-page-title-main">TRPC1</span> Protein and coding gene in humans

Transient receptor potential canonical 1 (TRPC1) is a protein that in humans is encoded by the TRPC1 gene.

<span class="mw-page-title-main">TRPC3</span> Protein and coding gene in humans

Short transient receptor potential channel 3 (TrpC3) also known as transient receptor protein 3 (TRP-3) is a protein that in humans is encoded by the TRPC3 gene. The TRPC3/6/7 subfamily are implicated in the regulation of vascular tone, cell growth, proliferation and pathological hypertrophy. These are diacylglycerol-sensitive cation channels known to regulate intracellular calcium via activation of the phospholipase C (PLC) pathway and/or by sensing Ca2+ store depletion. Together, their role in calcium homeostasis has made them potential therapeutic targets for a variety of central and peripheral pathologies.

<span class="mw-page-title-main">TRPC4</span> Protein and coding gene in humans

The short transient receptor potential channel 4 (TrpC4), also known as Trp-related protein 4, is a protein that in humans is encoded by the TRPC4 gene.

<span class="mw-page-title-main">TRPC5</span> Protein-coding gene in the species Homo sapiens

Short transient receptor potential channel 5 (TrpC5) also known as transient receptor protein 5 (TRP-5) is a protein that in humans is encoded by the TRPC5 gene. TrpC5 is subtype of the TRPC family of mammalian transient receptor potential ion channels.

<span class="mw-page-title-main">TRPM5</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M member 5 (TRPM5), also known as long transient receptor potential channel 5 is a protein that in humans is encoded by the TRPM5 gene.

<span class="mw-page-title-main">TRPV2</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily V member 2 is a protein that in humans is encoded by the TRPV2 gene. TRPV2 is a nonspecific cation channel that is a part of the TRP channel family. This channel allows the cell to communicate with its extracellular environment through the transfer of ions, and responds to noxious temperatures greater than 52 °C. It has a structure similar to that of potassium channels, and has similar functions throughout multiple species; recent research has also shown multiple interactions in the human body.

<span class="mw-page-title-main">NFATC4</span> Protein-coding gene in the species Homo sapiens

Nuclear factor of activated T-cells, cytoplasmic 4 is a protein that in humans is encoded by the NFATC4 gene.

<span class="mw-page-title-main">ITPR2</span> Protein-coding gene in humans

Inositol 1,4,5-trisphosphate receptor, type 2, also known as ITPR2, is a protein which in humans is encoded by the ITPR2 gene. The protein encoded by this gene is both a receptor for inositol triphosphate and a calcium channel.

Cenderitide is a natriuretic peptide developed by the Mayo Clinic as a potential treatment for heart failure. Cenderitide is created by the fusion of the 15 amino acid C-terminus of the snake venom dendroaspis natriuretic peptide (DNP) with the full C-type natriuretic peptide (CNP) structure. This peptide chimera is a dual activator of the natriuretic peptide receptors NPR-A and NPR-B and therefore exhibits the natriuretic and diuretic properties of DNP, as well as the antiproliferative and antifibrotic properties of CNP.

The transient receptor potential Ca2+ channel (TRP-CC) family (TC# 1.A.4) is a member of the voltage-gated ion channel (VIC) superfamily and consists of cation channels conserved from worms to humans. The TRP-CC family also consists of seven subfamilies (TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML) based on their amino acid sequence homology:

  1. the canonical or classic TRPs,
  2. the vanilloid receptor TRPs,
  3. the melastatin or long TRPs,
  4. ankyrin (whose only member is the transmembrane protein 1 [TRPA1])
  5. TRPN after the nonmechanoreceptor potential C (nonpC), and the more distant cousins,
  6. the polycystins
  7. and mucolipins.
<span class="mw-page-title-main">GSK417651A</span> Chemical compound

GSK417651A is a chemical compound which acts as a blocker of the TRPC family of calcium channels, with selectivity for the TRPC3 and TRPC6 subtypes. It has been used to investigate the role of TRPC3/6 channels in heart function.

Alexander G. Obukhov is an American researcher, who specializes in ion channels, molecular physiology, and vascular biology. Since 1986, Obukhov published research articles, with the most notable ones published in academic journals such as Nature, Journal of Biological Chemistry, EMBO Journal, Journal of Cell Biology, Proceedings of the National Academy of Sciences of the United States of America, and Neuron. Obukhov's research later evolved to feature multiple fields including neurophysiology, traumatic brain injury, pain, and atherosclerosis.

References

  1. 1 2 Nilius B, Owsianik G, Voets T, Peters JA (2007). "Transient receptor potential cation channels in disease". Physiol. Rev. 87 (1): 165–217. doi:10.1152/physrev.00021.2006. PMID   17237345.
  2. 1 2 Fowler, MA; Sidiropoulou, K; Ozkan, ED; Phillips, CW; Cooper, DC (2007). "Corticolimbic Expression of TRPC4 and TRPC5 Channels in the Rodent Brain". PLOS ONE. 2 (6): e573. Bibcode:2007PLoSO...2..573F. doi: 10.1371/journal.pone.0000573 . PMC   1892805 . PMID   17593972.
  3. ↑ Fowler, M; Varnell, A; Dietrich, A.; Birnbaumer, L.; Cooper, DC. (2012). "Deletion of the trpc1 gene and the effects on locomotor and conditioned place-preference responses to cocaine". Nature Precedings. doi: 10.1038/npre.2012.7153.1 (inactive 1 November 2024).{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  4. ↑ S. Z. Xu; P. Sukumar; F. Zeng; et al. (2008). "TRPC channel activation by extracellular thioredoxin". Nature. 451 (7174): 69–72. Bibcode:2008Natur.451...69X. doi:10.1038/nature06414. PMC   2645077 . PMID   18172497.
  5. ↑ Boulay G, Brown DM, Qin N, et al. (December 1999). "Modulation of Ca(2+) entry by polypeptides of the inositol 1,4, 5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion-activated Ca(2+) entry". Proc. Natl. Acad. Sci. U.S.A. 96 (26): 14955–60. doi: 10.1073/pnas.96.26.14955 . PMC   24754 . PMID   10611319.
  6. ↑ Lessard CB; Lussier MP; Cayouette S; Bourque G; Boulay G. (2005). "The overexpression of presenilin2 and Alzheimer's-disease-linked presenilin2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells". Cell Signal. 17 (4): 437–445. doi:10.1016/j.cellsig.2004.09.005. PMID   15601622.
  7. 1 2 3 4 5 Rowell, J.; Koitabashi, N.; Kass, D. (2010). "TRP-ing up heart and vessels: canonical transient receptor potentials and cardiovascular disease". Journal of Cardiovascular Translational Research. 3 (5): 516–524. doi:10.1007/s12265-010-9208-4. PMC   3875464 . PMID   20652467.
  8. 1 2 Yue, Z.; Zhang, Y.; Xie, J.; Jiang, J.; Yue, L. (2013). "Transient receptor potential (TRP) channels and cardiac fibrosis". Current Topics in Medicinal Chemistry. 13 (3): 270–282. doi:10.2174/1568026611313030005. PMC   3874073 . PMID   23432060.
  9. 1 2 3 4 Bush, E.; Hood, D.; Papst, P.; et al. (2006). "Mechanisms of signal transduction: canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling". The Journal of Biological Chemistry. 281 (44): 33487–33496. doi: 10.1074/jbc.M605536200 . PMID   16950785.
  10. ↑ Moran, M.; McAlexander, M.; Biro, T.; Szallasi, A. (2011). "Transient receptor potential channels as therapeutic targets". Nature Reviews. Drug Discovery. 10 (8): 601–620. doi:10.1038/nrd3456. PMID   21804597. S2CID   8809131.
  11. ↑ Smith, Richard (2009). "Excitatory actions of noradrenaline and metabotropic glutamate receptor activation in granule cells of the accessory olfactory bulb". Journal of Neurophysiology. 102 (2): 1103–1114. doi:10.1152/jn.91093.2008. PMC   2724365 . PMID   19474170.
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