Transient receptor potential cation channel, subfamily C, member 6 or Transient receptor potential canonical 6, also known as TRPC6, is a
humangene encoding a
protein of the same name. TRPC6 is a
transient receptor potential channel of the classical
TRPC subfamily.[5]
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]
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 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.[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
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
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]
^
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.
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^Müller WE, Singer A, Wonnemann M (July 2001). "Hyperforin--antidepressant activity by a novel mechanism of action". Pharmacopsychiatry. 34 (Suppl 1): S98-102.
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PMID11518085.
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^
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): 533–40.
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): 1777–9.
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): 427–50.
doi:
10.1124/pr.57.4.6.
PMID16382100.
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