TRPC6

Last updated

TRPC6
Identifiers
Aliases TRPC6 , FSGS2, TRP6, transient receptor potential cation channel subfamily C member 6
External IDs OMIM: 603652; MGI: 109523; HomoloGene: 37944; GeneCards: TRPC6; OMA:TRPC6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7225

22068

Ensembl

ENSG00000137672

ENSMUSG00000031997

UniProt

Q9Y210

Q61143

RefSeq (mRNA)

NM_004621

NM_001282086
NM_001282087
NM_013838

RefSeq (protein)

NP_004612

NP_001269015
NP_001269016
NP_038866

Location (UCSC) Chr 11: 101.45 – 101.87 Mb Chr 9: 8.54 – 8.68 Mb
PubMed search [3] [4]
Wikidata
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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. [5]

Contents

TRPC6 channels are nonselective cation channels that respond directly to diacylglycerol (DAG), a product of phospholipase C activity. This activation leads to cellular depolarization and calcium influx. [5] [6]

Unlike the closely related TRPC3 channels, TRPC6 channels possess the distinctive ability to transport heavy metal ions. TRPC6 channels facilitate the transport of zinc ions, promoting their accumulation inside cells. [6] [7] In addition, despite their non-selectiveness, TRPC6 exhibits a strong preference for calcium ions, with a permeability ratio of calcium to sodium (PCa/PNa) of roughly six. This selectivity is significantly higher compared to TRPC3, which displays a weaker preference for calcium with a (PCa/PNa) ratio of only 1.1. [6]

Function

TRPC6 channels are widely distributed in the human body and are emerging as crucial regulators of several key physiological functions:

In blood vessels

Small arteries and arterioles exhibit a self-regulatory mechanism called myogenic tone, enabling them to maintain relatively stable blood flow despite fluctuating intravascular pressures. [8] When intravascular pressure within a small artery or arteriole increases, the vessel walls automatically constrict. This narrowing reduces blood flow, effectively counteracting the rising pressure and stabilizing overall flow. Conversely, if blood pressure suddenly drops, vasodilation occurs to allow more blood flow and compensate for the decrease. [9]

TRPC6 channels are present both in endothelial and smooth muscle cells, [8] and their function is similar to α‑adrenoreceptors; they are both involved in vasoconstriction. [9] However, TPRC6-mediated vasoconstriction is mechanosensetive (i.e. activated by mechanical stimulation) and these channels are involved in maintenance of the myogenic tone of blood vessels and autoregulation of blood flow. [8]

When intravascular blood pressure rises, this causes stretching of the walls of blood vessels. This mechanical stretch activates the TRPC6 channel. Once activated, TRPC6 allows Ca2+ to enter the smooth muscle cells. This increase in intracellular Ca2+ triggers a chain reaction leading to vasoconstriction. [6]

In the kidneys

TRPC6 channels are extensively present throughout the kidney, both in the tubular segments and the glomeruli. Within the glomeruli, expression of TRPC6 is primarily concentrated in podocytes. [10] Despite being extensively expressed throughout the kidneys and despite the established link between TRPC6 over-activation and kidney pathologies, the physiological roles of this channel in healthy kidney function remain less understood. [11] [12] Podocytes normally display minimal baseline activity of TRPC6 channels and TRPC6 knockout mice have not shown any evident changes in glomerular structure or filtration. [11]

Nevertheless, it has been hypothesized that the function of TRPC6 channels in podocytes resembles their function in smooth muscles of blood vessels. [13] [14]

Glomerular capillaries operate under significantly higher pressure than most other capillary beds. [14] When podocytes are stretched by glomerular capillary pressure, mechanosensitive TRPC6 channels trigger a surge in Ca2+ influx into podocytes, causing them to contract. [13] [15] [16] [17] This podocyte contraction exerts a force that opposes capillary wall overstretching and distention, that would otherwise lead to protein leakage. [14]

However, in order to control the degree of podocyte contraction and maintain blood vessel patency, the influx of Ca2+ mediated by TRPC6 channels is accompanied by an increase in the activity of big potassium (BK) channels, leading to the efflux of K+. BK channel activation and the resultant K+ efflux mitigate and counteract the depolarization induced by TRPC6 activation, potentially serving as a protective mechanism through regulation of membrane depolarization and limiting podocyte contraction. [13] [18]

As shown in the left portion of the figure, angiotensin II (Ang II) activates phospholipase C (PLC), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates TRPC6 channels, and IP3 binds to its receptor on the endoplasmic reticulum. Both DAG and IP3 lead to increased cytosolic calcium concentration. This, in turn, leads to activation of BK channels, and subsequently K efflux. The upper side of the figure illustrates that TRPC6 interaction with podocyte-specific proteins such as nephrin, podocin and CD2AP allows this channel to be mechanosensitive, and hence TRPC6 channels can be activated by both chemical and mechanical stimuli. TRPCandBK.jpg
As shown in the left portion of the figure, angiotensin II (Ang II) activates phospholipase C (PLC), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates TRPC6 channels, and IP3 binds to its receptor on the endoplasmic reticulum. Both DAG and IP3 lead to increased cytosolic calcium concentration. This, in turn, leads to activation of BK channels, and subsequently K efflux. The upper side of the figure illustrates that TRPC6 interaction with podocyte-specific proteins such as nephrin, podocin and CD2AP allows this channel to be mechanosensitive, and hence TRPC6 channels can be activated by both chemical and mechanical stimuli.

In the central nervous system

Research of learning and memory mechanisms suggests that a continuous increase in the strength of synaptic transmission is necessary to achieve long-term modification of neural network properties and memory storage. TRPC6 appears to be essential for the formation of an excitatory synapse; overexpressing TRPC6 greatly increased dendritic spine density and the level of synapsin I and PSD-95 cluster, known as the pre- and postsynaptic markers. [19]

TRPC6 has also been proven to participate in neuroprotection and its neuroprotective effect could be explained due to the antagonism of extrasynaptic NMDA receptor (NMDAR)-mediated intracellular calcium overload. TRPC6 activates calcineurin, which impedes the NMDAR activity. [19]

Hyperactivation of NMDAR is a critical event in glutamate-driven excitotoxicity that causes a rapid increase in intracellular calcium concentration. Such rapid increases in cytoplasmic calcium concentrations may activate and over-stimulate a variety of proteases, kinases, endonucleases, etc. This downstream neurotoxic cascade may trigger severe damage to neuronal functioning. Hyperactivation of NMDAR is frequently observed during brain ischemia and late stage Alzheimer's disease. [19]

Clinical significance

Since TRPC6 channels play a multifaceted role by participating in various signaling pathways, these channels are emerging as key players in the pathogenesis of a wide range of diseases including: [20]

  1. Kidney diseases
  2. Disorders of the nervous system
  3. Cancers
  4. Cardiovascular diseases
  5. Pulmonary diseases

Interactions

TRPC6 has been shown to interact with:

Ligands

Two of the primary active constituents responsible for the antidepressant and anxiolytic benefits of Hypericum perforatum , also known as St. John's Wort, are hyperforin and adhyperforin. [24] [25] These compounds are inhibitors of the reuptake of serotonin, norepinephrine, dopamine, γ-aminobutyric acid, and glutamate, and they are reported to exert these effects by binding to and activating TRPC6. [25] [26] Recent results with hyperforin have cast doubt on these findings as similar currents are seen upon Hyperforin treatment regardless of the presence of TRPC6. [27]

Related Research Articles

<span class="mw-page-title-main">Ion channel</span> Pore-forming membrane protein

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

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.

Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissues and participate in different signaling pathways involving calcium release from intracellular organelles. The RYR2 ryanodine receptor isoform is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.

<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.

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

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">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">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">TRPM2</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel, subfamily M, member 2, also known as TRPM2, is a protein that in humans is encoded by the TRPM2 gene.

<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">TRPM4</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M member 4 (hTRPM4), also known as melastatin-4, is a protein that in humans is encoded by the TRPM4 gene.

<span class="mw-page-title-main">TRPV4</span> Protein-coding gene in humans

Transient receptor potential cation channel subfamily V member 4 is an ion channel protein that in humans is encoded by the TRPV4 gene.

<span class="mw-page-title-main">TRPM8</span> Protein-coding gene in humans

Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. In addition, mints can desensitize a region through the activation of TRPM8 receptors.

<span class="mw-page-title-main">TRPM3</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M member 3 is a protein that in humans is encoded by the TRPM3 gene.

<span class="mw-page-title-main">TRPV5</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily V member 5 is a calcium channel protein that in humans is encoded by the TRPV5 gene.

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.

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 3 GRCh38: Ensembl release 89: ENSG00000137672 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031997 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Tang Q, Guo W, Zheng L, Wu JX, Liu M, Zhou X, et al. (July 2018). "Structure of the receptor-activated human TRPC6 and TRPC3 ion channels". Cell Research. 28 (7): 746–755. doi: 10.1038/s41422-018-0038-2 . PMC   6028632 . PMID   29700422.
  6. 1 2 3 4 Dietrich A, Gudermann T (2014). "TRPC6: Physiological Function and Pathophysiological Relevance". Mammalian Transient Receptor Potential (TRP) Cation Channels. Handbook of Experimental Pharmacology. Vol. 222. pp. 157–88. doi: 10.1007/978-3-642-54215-2_7 . ISBN   978-3-642-54214-5. PMID   24756706.
  7. ↑ Oda S, Nishiyama K, Furumoto Y, Yamaguchi Y, Nishimura A, Tang X, et al. (October 2022). "Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors". Nature Communications. 13 (1): 6374. Bibcode:2022NatCo..13.6374O. doi:10.1038/s41467-022-34194-9. PMC   9606288 . PMID   36289215.
  8. 1 2 3 Brayden JE, Earley S, Nelson MT, Reading S (September 2008). "Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow". Clinical and Experimental Pharmacology & Physiology. 35 (9): 1116–1120. doi:10.1111/j.1440-1681.2007.04855.x. PMC   4193799 . PMID   18215190.
  9. 1 2 Abdinghoff J, Servello D, Jacobs T, Beckmann A, Tschernig T (May 2022). "Evaluation of the presence of TRPC6 channels in human vessels: A pilot study using immunohistochemistry". Biomedical Reports. 16 (5): 42. doi:10.3892/br.2022.1525. PMC   8972230 . PMID   35371476.
  10. ↑ Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, et al. (July 2005). "TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function". Nature Genetics. 37 (7): 739–744. doi:10.1038/ng1592. PMC   1360984 . PMID   15924139.
  11. 1 2 Tomilin V, Mamenko M, Zaika O, Pochynyuk O (May 2016). "Role of renal TRP channels in physiology and pathology". Seminars in Immunopathology. 38 (3): 371–383. doi:10.1007/s00281-015-0527-z. PMC   4798925 . PMID   26385481.
  12. ↑ Kanthakumar P, Adebiyi A (2021). "Renal vascular TRP channels". Current Research in Physiology. 4: 17–23. doi:10.1016/j.crphys.2021.02.001. PMC   8225244 . PMID   34179830.
  13. 1 2 3 Morton MJ, Hutchinson K, Mathieson PW, Witherden IR, Saleem MA, Hunter M (December 2004). "Human podocytes possess a stretch-sensitive, Ca2+-activated K+ channel: potential implications for the control of glomerular filtration". Journal of the American Society of Nephrology. 15 (12): 2981–2987. doi: 10.1097/01.ASN.0000145046.24268.0D . PMID   15579500.
  14. 1 2 3 Dryer SE, Reiser J (October 2010). "TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology". American Journal of Physiology. Renal Physiology. 299 (4): F689–F701. doi:10.1152/ajprenal.00298.2010. PMC   2957253 . PMID   20685822.
  15. ↑ Welsh GI, Saleem MA (25 October 2011). "The podocyte cytoskeleton--key to a functioning glomerulus in health and disease". Nature Reviews. Nephrology. 8 (1): 14–21. doi: 10.1038/nrneph.2011.151 . PMID   22025085. In these lipid microdomains, podocin clusters and regulates the ion channel TRPC6 and it has been suggested that this regulation gives the slit diaphragm the ability to act as a mechanosensor that enables the podocyte to remodel its cytoskeleton and contract its foot processes in response to mechanical stimuli.
  16. ↑ Carlström M, Wilcox CS, Arendshorst WJ (April 2015). "Renal autoregulation in health and disease". Physiological Reviews. 95 (2): 405–511. doi:10.1152/physrev.00042.2012. PMC   4551215 . PMID   25834230.
  17. ↑ Tian D, Jacobo SM, Billing D, Rozkalne A, Gage SD, Anagnostou T, et al. (October 2010). "Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels". Science Signaling. 3 (145): ra77. doi:10.1126/scisignal.2001200. PMC   3071756 . PMID   20978238.
  18. ↑ Hu S, Han R, Chen L, Qin W, Xu X, Shi J, et al. (March 2021). "Upregulated LRRC55 promotes BK channel activation and aggravates cell injury in podocytes". The Journal of Experimental Medicine. 218 (3). doi:10.1084/jem.20192373. PMC   7756252 . PMID   33346797.
  19. 1 2 3 Zernov N, Popugaeva E (October 2023). "Role of Neuronal TRPC6 Channels in Synapse Development, Memory Formation and Animal Behavior". International Journal of Molecular Sciences. 24 (20): 15415. doi: 10.3390/ijms242015415 . PMC   10607207 . PMID   37895105. Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  20. ↑ Saqib U, Munjuluri S, Sarkar S, Biswas S, Mukherjee O, Satsangi H, et al. (August 2023). "Transient Receptor Potential Canonical 6 (TRPC6) Channel in the Pathogenesis of Diseases: A Jack of Many Trades". Inflammation. 46 (4): 1144–1160. doi:10.1007/s10753-023-01808-3. PMC   10112830 . PMID   37072606.
  21. ↑ Hisatsune C, Kuroda Y, Nakamura K, Inoue T, Nakamura T, Michikawa T, et al. (April 2004). "Regulation of TRPC6 channel activity by tyrosine phosphorylation". The Journal of Biological Chemistry. 279 (18): 18887–18894. doi: 10.1074/jbc.M311274200 . PMID   14761972.
  22. ↑ Chu X, Tong Q, Cheung JY, Wozney J, Conrad K, Mazack V, et al. (March 2004). "Interaction of TRPC2 and TRPC6 in erythropoietin modulation of calcium influx". The Journal of Biological Chemistry. 279 (11): 10514–10522. doi: 10.1074/jbc.M308478200 . PMID   14699131.
  23. ↑ Hofmann T, Schaefer M, Schultz G, Gudermann T (May 2002). "Subunit composition of mammalian transient receptor potential channels in living cells". Proceedings of the National Academy of Sciences of the United States of America. 99 (11): 7461–7466. Bibcode:2002PNAS...99.7461H. doi: 10.1073/pnas.102596199 . PMC   124253 . PMID   12032305.
  24. ↑ Müller WE, Singer A, Wonnemann M (July 2001). "Hyperforin--antidepressant activity by a novel mechanism of action". Pharmacopsychiatry. 34 (Suppl 1): S98-102. doi:10.1055/s-2001-15512. PMID   11518085. S2CID   21872392.
  25. 1 2 Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Müller WE (1998). "Hyperforin as a possible antidepressant component of hypericum extracts". Life Sciences. 63 (6): 499–510. doi:10.1016/S0024-3205(98)00299-9. PMID   9718074.
  26. ↑ Leuner K, Kazanski V, Müller M, Essin K, Henke B, Gollasch M, et al. (December 2007). "Hyperforin--a key constituent of St. John's wort specifically activates TRPC6 channels". FASEB Journal. 21 (14): 4101–4111. doi: 10.1096/fj.07-8110com . PMID   17666455. S2CID   14097884.
  27. ↑ Sell TS, Belkacemi T, Flockerzi V, Beck A (December 2014). "Protonophore properties of hyperforin are essential for its pharmacological activity". Scientific Reports. 4: 7500. Bibcode:2014NatSR...4E7500S. doi:10.1038/srep07500. PMC   4266863 . PMID   25511254.

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