TRPC6
Transient receptor potential cation channel, subfamily C, member 6 or Transient receptor potential canonical 6, also known as TRPC6, is a human gene encoding a protein of the same name. TRPC6 is a transient receptor potential channel of the classical TRPC subfamily.[5]
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
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TRPC6 channels are widely distributed in the human body and are emerging as crucial regulators of several key physiological functions:
In blood vessels
[edit]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 central nervous system
[edit]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.[10]
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.[10]
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.[10]
In the kidneys
[edit]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.[11] 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.[12][13] Podocytes normally display minimal baseline activity of TRPC6 channels and TRPC6 knockout mice have not shown any evident changes in glomerular structure or filtration.[12]
Clinical significance
[edit]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:[14]
- Kidney diseases
- Disorders of the nervous system
- Cancers
- Cardiovascular diseases
- Pulmonary diseases
Interactions
[edit]TRPC6 has been shown to interact with:
Ligands
[edit]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.[18][19] 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.[19][20] Recent results with hyperforin have cast doubt on these findings as similar currents are seen upon Hyperforin treatment regardless of the presence of TRPC6.[21]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000137672 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031997 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b Tang Q, Guo W, Zheng L, Wu JX, Liu M, Zhou X, Zhang X, Chen L (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.
- ^ a b c d 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.
- ^ Oda S, Nishiyama K, Furumoto Y, Yamaguchi Y, Nishimura A, Tang X, Kato Y, Numaga-Tomita T, Kaneko T, Mangmool S, Kuroda T, Okubo R, Sanbo M, Hirabayashi M, Sato Y, Nakagawa Y, Kuwahara K, Nagata R, Iribe G, Mori Y, Nishida M (26 October 2022). "Myocardial TRPC6-mediated Zn(2+) influx induces beneficial positive inotropy through β-adrenoceptors". Nature Communications. 13 (1): 6374. doi:10.1038/s41467-022-34194-9. PMC 9606288. PMID 36289215.
- ^ a b c 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): 1116–20. doi:10.1111/j.1440-1681.2007.04855.x. PMC 4193799. PMID 18215190.
- ^ a b 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.
- ^ a b c Zernov N, Popugaeva E (21 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.
This article incorporates text available under the CC BY 4.0 license.
- ^ Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R, Mundel P, Smith PL, Clapham DE, Pollak MR (July 2005). "TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function". Nature Genetics. 37 (7): 739–44. doi:10.1038/ng1592. PMC 1360984. PMID 15924139.
- ^ a b Tomilin V, Mamenko M, Zaika O, Pochynyuk O (May 2016). "Role of renal TRP channels in physiology and pathology". Seminars in Immunopathology. 38 (3): 371–83. doi:10.1007/s00281-015-0527-z. PMC 4798925. PMID 26385481.
- ^ 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.
- ^ Saqib U, Munjuluri S, Sarkar S, Biswas S, Mukherjee O, Satsangi H, Baig MS, Obukhov AG, Hajela K (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.
- ^ Hisatsune C, Kuroda Y, Nakamura K, Inoue T, Nakamura T, Michikawa T, Mizutani A, Mikoshiba K (April 2004). "Regulation of TRPC6 channel activity by tyrosine phosphorylation". The Journal of Biological Chemistry. 279 (18): 18887–94. doi:10.1074/jbc.M311274200. PMID 14761972.
- ^ Chu X, Tong Q, Cheung JY, Wozney J, Conrad K, Mazack V, Zhang W, Stahl R, Barber DL, Miller BA (March 2004). "Interaction of TRPC2 and TRPC6 in erythropoietin modulation of calcium influx". The Journal of Biological Chemistry. 279 (11): 10514–22. doi:10.1074/jbc.M308478200. PMID 14699131.
- ^ 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): 7461–6. Bibcode:2002PNAS...99.7461H. doi:10.1073/pnas.102596199. PMC 124253. PMID 12032305.
- ^ 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.
- ^ a b 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.
- ^ Leuner K, Kazanski V, Müller M, Essin K, Henke B, Gollasch M, Harteneck C, Müller WE (December 2007). "Hyperforin--a key constituent of St. John's wort specifically activates TRPC6 channels". FASEB Journal. 21 (14): 4101–11. doi:10.1096/fj.07-8110com. PMID 17666455. S2CID 14097884.
- ^ 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.
Further reading
[edit]- Heiner I, Eisfeld J, Lückhoff A (2004). "Role and regulation of TRP channels in neutrophil granulocytes". Cell Calcium. 33 (5–6): 533–40. doi:10.1016/S0143-4160(03)00058-7. PMID 12765698.
- Walz G (September 2005). "Slit or pore? A mutation of the ion channel TRPC6 causes FSGS". Nephrology, Dialysis, Transplantation. 20 (9): 1777–9. doi:10.1093/ndt/gfh961. PMID 15998650.
- Clapham DE, Julius D, Montell C, Schultz G (December 2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacological Reviews. 57 (4): 427–50. doi:10.1124/pr.57.4.6. PMID 16382100. S2CID 17936350.
- Schlöndorff JS, Pollak MR (December 2006). "TRPC6 in glomerular health and disease: what we know and what we believe". Seminars in Cell & Developmental Biology. 17 (6): 667–74. doi:10.1016/j.semcdb.2006.11.003. PMC 2705932. PMID 17116414.
- Dietrich A, Gudermann T (2007). "TRPC6". Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology. Vol. 179. pp. 125–41. doi:10.1007/978-3-540-34891-7_7. ISBN 978-3-540-34889-4. PMID 17217054.
External links
[edit]- TRPC6+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)