Biology:TRPC6

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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.[1]

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.[1][2]

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.[2][3] In addition, despite their non-selectiveness, TRPC6 exhibits a strong preference for calcium ions, with a permeability ratio of calcium to sodium (Template:Base/Template:Base) of roughly six. This selectivity is significantly higher compared to TRPC3, which displays a weaker preference for calcium with a (Template:Base/Template:Base) ratio of only 1.1.[2]

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.[4] 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.[5]

TRPC6 channels are present both in endothelial and smooth muscle cells,[4] and their function is similar to α‑adrenoreceptors; they are both involved in vasoconstriction.[5] 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.[4]

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.[2]

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.[6] 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.[7][8] Podocytes normally display minimal baseline activity of TRPC6 channels and TRPC6 knockout mice have not shown any evident changes in glomerular structure or filtration.[7]

Nevertheless, it has been hypothesized that the function of TRPC6 channels in podocytes resembles their function in smooth muscles of blood vessels.[9][10]

Glomerular capillaries operate under significantly higher pressure than most other capillary beds.[10] When podocytes are stretched by glomerular capillary pressure, mechanosensitive TRPC6 channels trigger a surge in Ca2+ influx into podocytes, causing them to contract.[9][11][12][13] This podocyte contraction exerts a force that opposes capillary wall overstretching and distention, that would otherwise lead to protein leakage.[10]

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.[9][14]

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.[15]

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.[15]

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.[15]

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:[16]

  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.[20][21] 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.[21][22] Recent results with hyperforin have cast doubt on these findings as similar currents are seen upon Hyperforin treatment regardless of the presence of TRPC6.[23]

References

  1. ↑ 1.0 1.1 "Structure of the receptor-activated human TRPC6 and TRPC3 ion channels". Cell Research 28 (7): 746–755. July 2018. doi:10.1038/s41422-018-0038-2. PMID 29700422. 
  2. ↑ 2.0 2.1 2.2 2.3 "TRPC6: Physiological Function and Pathophysiological Relevance". Mammalian Transient Receptor Potential (TRP) Cation Channels. Handbook of Experimental Pharmacology. 222. 2014. pp. 157–88. doi:10.1007/978-3-642-54215-2_7. ISBN 978-3-642-54214-5. 
  3. ↑ "Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors". Nature Communications 13 (1): 6374. October 2022. doi:10.1038/s41467-022-34194-9. PMID 36289215. Bibcode: 2022NatCo..13.6374O. 
  4. ↑ 4.0 4.1 4.2 "Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow". Clinical and Experimental Pharmacology & Physiology 35 (9): 1116–1120. September 2008. doi:10.1111/j.1440-1681.2007.04855.x. PMID 18215190. 
  5. ↑ 5.0 5.1 "Evaluation of the presence of TRPC6 channels in human vessels: A pilot study using immunohistochemistry". Biomedical Reports 16 (5): 42. May 2022. doi:10.3892/br.2022.1525. PMID 35371476. 
  6. ↑ "TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function". Nature Genetics 37 (7): 739–744. July 2005. doi:10.1038/ng1592. PMID 15924139. 
  7. ↑ 7.0 7.1 "Role of renal TRP channels in physiology and pathology". Seminars in Immunopathology 38 (3): 371–383. May 2016. doi:10.1007/s00281-015-0527-z. PMID 26385481. 
  8. ↑ "Renal vascular TRP channels". Current Research in Physiology 4: 17–23. 2021. doi:10.1016/j.crphys.2021.02.001. PMID 34179830. 
  9. ↑ 9.0 9.1 9.2 "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. December 2004. doi:10.1097/01.ASN.0000145046.24268.0D. PMID 15579500. 
  10. ↑ 10.0 10.1 10.2 "TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology". American Journal of Physiology. Renal Physiology 299 (4): F689–F701. October 2010. doi:10.1152/ajprenal.00298.2010. PMID 20685822. 
  11. ↑ "The podocyte cytoskeleton--key to a functioning glomerulus in health and disease". Nature Reviews. Nephrology 8 (1): 14–21. October 2011. 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.". 
  12. ↑ "Renal autoregulation in health and disease". Physiological Reviews 95 (2): 405–511. April 2015. doi:10.1152/physrev.00042.2012. PMID 25834230. 
  13. ↑ "Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels". Science Signaling 3 (145): ra77. October 2010. doi:10.1126/scisignal.2001200. PMID 20978238. 
  14. ↑ "Upregulated LRRC55 promotes BK channel activation and aggravates cell injury in podocytes". The Journal of Experimental Medicine 218 (3). March 2021. doi:10.1084/jem.20192373. PMID 33346797. 
  15. ↑ 15.0 15.1 15.2 "Role of Neuronal TRPC6 Channels in Synapse Development, Memory Formation and Animal Behavior". International Journal of Molecular Sciences 24 (20). October 2023. doi:10.3390/ijms242015415. PMID 37895105.  This article incorporates text available under the CC BY 4.0 license.
  16. ↑ "Transient Receptor Potential Canonical 6 (TRPC6) Channel in the Pathogenesis of Diseases: A Jack of Many Trades". Inflammation 46 (4): 1144–1160. August 2023. doi:10.1007/s10753-023-01808-3. PMID 37072606. 
  17. ↑ "Regulation of TRPC6 channel activity by tyrosine phosphorylation". The Journal of Biological Chemistry 279 (18): 18887–18894. April 2004. doi:10.1074/jbc.M311274200. PMID 14761972. 
  18. ↑ "Interaction of TRPC2 and TRPC6 in erythropoietin modulation of calcium influx". The Journal of Biological Chemistry 279 (11): 10514–10522. March 2004. doi:10.1074/jbc.M308478200. PMID 14699131. 
  19. ↑ "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. May 2002. doi:10.1073/pnas.102596199. PMID 12032305. Bibcode: 2002PNAS...99.7461H. 
  20. ↑ "Hyperforin--antidepressant activity by a novel mechanism of action". Pharmacopsychiatry 34 (Suppl 1): S98-102. July 2001. doi:10.1055/s-2001-15512. PMID 11518085. 
  21. ↑ 21.0 21.1 "Hyperforin as a possible antidepressant component of hypericum extracts". Life Sciences 63 (6): 499–510. 1998. doi:10.1016/S0024-3205(98)00299-9. PMID 9718074. 
  22. ↑ "Hyperforin--a key constituent of St. John's wort specifically activates TRPC6 channels". FASEB Journal 21 (14): 4101–4111. December 2007. doi:10.1096/fj.07-8110com. PMID 17666455. 
  23. ↑ "Protonophore properties of hyperforin are essential for its pharmacological activity". Scientific Reports 4: 7500. December 2014. doi:10.1038/srep07500. PMID 25511254. Bibcode: 2014NatSR...4E7500S. 

Further reading



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