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]
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TRPC6 channels are widely distributed in the human body and are emerging as crucial regulators of several key physiological functions:
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’re 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]
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]
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 haven’t shown any evident changes in glomerular structure or filtration. [12]
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]
TRPC6 has been shown to interact with:
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]
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.
TRPV6 is a membrane calcium (Ca2+) channel protein which is particularly involved in the first step in Ca2+absorption in the intestine.
In the physiology of the kidney, tubuloglomerular feedback (TGF) is a feedback system inside the kidneys. Within each nephron, information from the renal tubules is signaled to the glomerulus. Tubuloglomerular feedback is one of several mechanisms the kidney uses to regulate glomerular filtration rate (GFR). It involves the concept of purinergic signaling, in which an increased distal tubular sodium chloride concentration causes a basolateral release of adenosine from the macula densa cells. This initiates a cascade of events that ultimately brings GFR to an appropriate level.
TRPC is a family of transient receptor potential cation channels in animals.
TRPV is a family of transient receptor potential cation channels in animals. All TRPVs are highly calcium selective.
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.
TRPP is a family of transient receptor potential ion channels which when mutated can cause polycystic kidney disease.
Transient receptor potential canonical 1 (TRPC1) is a protein that in humans is encoded by the TRPC1 gene.
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.
The short transient receptor potential channel 4 (TrpC4), also known as Trp-related protein 4, is a protein that in humans is encoded by the TRPC4 gene.
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.
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.
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.
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.
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.
Transient receptor potential cation channel subfamily M member 3 is a protein that in humans is encoded by the TRPM3 gene.
Transient receptor potential cation channel, subfamily M, member 7, also known as TRPM7, is a human gene encoding a protein of the same name.
Transient receptor potential cation channel subfamily V member 5 is a calcium channel protein that in humans is encoded by the TRPV5 gene.
Polycystin-2(PC2) is a protein that in humans is encoded by the PKD2 gene.
GSK417651A is a chemical compound which acts as a blocker of the TRPC family of calcium channels, with selectivity for the TRPC3 and TRPC6 subtypes. It has been used to investigate the role of TRPC3/6 channels in heart function.