Transient receptor potential cation channel, subfamily C, member 6 orTransient receptor potential canonical 6, also known asTRPC6, is a protein encoded in the human by theTRPC6gene. TRPC6 is atransient receptor potential channel of the classicalTRPC subfamily.[5]
Unlike the closely relatedTRPC3 channels, TRPC6 channels possess the distinctive ability to transportheavy metal ions. TRPC6 channels facilitate the transport ofzinc 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]
Small arteries andarterioles exhibit a self-regulatory mechanism calledmyogenic tone, enabling them to maintain relatively stable blood flow despite fluctuatingintravascular pressures.[8] When intravascular pressure within a small artery or arteriole increases, the vessel walls automaticallyconstrict. 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 inendothelial andsmooth muscle cells,[8] and their function is similar toα‑adrenoreceptors; they are both involved in vasoconstriction.[9] However, TPRC6-mediated vasoconstriction ismechanosensetive (i.e. activated by mechanical stimulation) and these channels are involved in maintenance of themyogenic 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+ triggersa chain reaction leading to vasoconstriction.[6]
TRPC6 channels are extensively present throughout the kidney, both in thetubular segments and theglomeruli. Within the glomeruli, expression of TRPC6 is primarily concentrated inpodocytes.[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 TRPC6knockout 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 ofbig 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) activatesphospholipase C (PLC), which cleavesphosphatidylinositol 4,5-bisphosphate (PIP2) intodiacyl glycerol (DAG) andinositol 1,4,5-trisphosphate (IP3). DAG activates TRPC6 channels, and IP3 binds to its receptor on theendoplasmic 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 asnephrin,podocin andCD2AP allows this channel to be mechanosensitive, and hence TRPC6 channels can be activated by both chemical and mechanical stimuli.
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 increaseddendritic spine density and the level ofsynapsin I andPSD-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 extrasynapticNMDA receptor (NMDAR)-mediated intracellular calcium overload. TRPC6 activatescalcineurin, which impedes the NMDAR activity.[19]
Hyperactivation of NMDAR is a critical event inglutamate-drivenexcitotoxicity that causes a rapid increase in intracellular calcium concentration. Such rapid increases in cytoplasmic calcium concentrations may activate and over-stimulate a variety ofproteases,kinases,endonucleases, etc. This downstream neurotoxic cascade may trigger severe damage to neuronal functioning. Hyperactivation of NMDAR is frequently observed duringbrain ischemia and late stageAlzheimer's disease.[19]
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]
^abcdDietrich 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.ISBN978-3-642-54214-5.PMID24756706.
^Welsh GI, Saleem MA (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.PMID22025085.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.
^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.PMID11518085.S2CID21872392.
^abChatterjee 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.PMID9718074.
Heiner I, Eisfeld J, Lückhoff A (2004). "Role and regulation of TRP channels in neutrophil granulocytes".Cell Calcium.33 (5–6):533–540.doi:10.1016/S0143-4160(03)00058-7.PMID12765698.
Walz G (September 2005). "Slit or pore? A mutation of the ion channel TRPC6 causes FSGS".Nephrology, Dialysis, Transplantation.20 (9):1777–1779.doi:10.1093/ndt/gfh961.PMID15998650.
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):427–450.doi:10.1124/pr.57.4.6.PMID16382100.S2CID17936350.
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