{"history":[],"article":{"id":"9bc3bebc-80cd-4b49-af89-1aa671ab5e4d","title":"TRPC6","slug":"trpc6","content":":::summary\n:::\n\n# \n**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](https://bliptext.com/articles/gene).\n[TRPC](https://bliptext.com/articles/trpc)6 is a [transient receptor potential channel](https://bliptext.com/articles/transient-receptor-potential-channel) of the classical [TRPC](https://bliptext.com/articles/trpc) subfamily.\nTRPC6 channels are **nonselective** [cation channels](https://bliptext.com/articles/cation-channel-superfamily) that respond directly to [diacylglycerol](https://bliptext.com/articles/diglyceride) (DAG), a product of [phospholipase C](https://bliptext.com/articles/phospholipase-c) activity.\nThis activation leads to cellular [depolarization](https://bliptext.com/articles/depolarization) and [calcium](https://bliptext.com/articles/calcium) influx.\nUnlike the closely related [TRPC3](https://bliptext.com/articles/trpc3) channels, TRPC6 channels possess the distinctive ability to transport [heavy metal](https://bliptext.com/articles/heavy-metals) ions.\nTRPC6 channels facilitate the transport of [zinc](https://bliptext.com/articles/zinc) ions, promoting their accumulation inside cells.\nIn addition, despite their non-selectiveness, TRPC6 exhibits a strong preference for calcium ions, with a permeability ratio of calcium to sodium (/) of roughly six.\nThis selectivity is significantly higher compared to TRPC3, which displays a weaker preference for calcium with a (/) ratio of only 1.1.\n\n# Function\n**TRPC6 channels are widely distributed in the human body and are emerging as crucial regulators of several key physiological functions:**\n\n## In blood vessels\nSmall arteries and [arterioles](https://bliptext.com/articles/arterioles) exhibit a self-regulatory mechanism called [myogenic tone](https://bliptext.com/articles/myogenic-mechanism), enabling them to maintain relatively stable blood flow despite fluctuating [intravascular pressures](https://bliptext.com/articles/blood-pressure).\nWhen intravascular pressure within a small artery or arteriole increases, the vessel walls automatically [constrict](https://bliptext.com/articles/vasoconstriction).\nThis narrowing reduces blood flow, effectively counteracting the rising pressure and stabilizing overall flow.\nConversely, if blood pressure suddenly drops, [vasodilation](https://bliptext.com/articles/vasodilation) occurs to allow more blood flow and compensate for the decrease.\nTRPC6 channels are present both in [endothelial](https://bliptext.com/articles/endothelium) and [smooth muscle](https://bliptext.com/articles/smooth-muscle) cells, and their function is similar to [α‑adrenoreceptors](https://bliptext.com/articles/alpha-1-adrenergic-receptor); they are both involved in vasoconstriction.\nHowever, TPRC6-mediated vasoconstriction is [mechanosensetive](https://bliptext.com/articles/mechanosensitive-channels) (i.e. activated by mechanical stimulation) and these channels are involved in maintenance of the [myogenic tone](https://bliptext.com/articles/myogenic-mechanism) of blood vessels and autoregulation of blood flow.\nWhen intravascular blood pressure rises, this causes stretching of the walls of blood vessels.\nThis mechanical stretch activates the TRPC6 channel.\nOnce activated, TRPC6 allows Ca2+ to enter the smooth muscle cells.\nThis increase in intracellular Ca2+ triggers [a chain reaction](https://bliptext.com/articles/vasoconstriction) leading to vasoconstriction.\n\n## In the kidneys\nTRPC6 channels are extensively present throughout the kidney, both in the [tubular segments](https://bliptext.com/articles/nephron) and the [glomeruli](https://bliptext.com/articles/glomerulus-kidney).\nWithin the glomeruli, expression of TRPC6 is primarily concentrated in [podocytes](https://bliptext.com/articles/podocytes).\nDespite 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.\nPodocytes normally display minimal baseline activity of TRPC6 channels and TRPC6 [knockout mice](https://bliptext.com/articles/knockout-mouse) have not shown any evident changes in glomerular structure or filtration.\nNevertheless, it has been hypothesized that the function of TRPC6 channels in podocytes resembles their function in smooth muscles of blood vessels.\nGlomerular capillaries operate under significantly higher pressure than most other capillary beds.\nWhen podocytes are stretched by glomerular capillary pressure, mechanosensitive TRPC6 channels trigger a surge in Ca2+ influx into podocytes, causing them to contract.\nThis podocyte contraction exerts a force that opposes capillary wall overstretching and distention, that would otherwise lead to protein leakage.\nHowever, 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](https://bliptext.com/articles/bk-channel), leading to the efflux of K+.\nBK 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.\nTRPCandBK.jpg (Ang II) activates [phospholipase C](https://bliptext.com/articles/phospholipase-c) (PLC), which cleaves [phosphatidylinositol 4,5-bisphosphate](https://bliptext.com/articles/phosphatidylinositol-4-5-bisphosphate) (PIP2) into [diacyl glycerol](https://bliptext.com/articles/diacyl-glycerol) (DAG) and [inositol 1,4,5-trisphosphate](https://bliptext.com/articles/inositol-1-4-5-trisphosphate) (IP3). DAG activates TRPC6 channels, and IP3 binds to its receptor on the [endoplasmic reticulum](https://bliptext.com/articles/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.\nThe upper side of the figure illustrates that TRPC6 interaction with podocyte-specific proteins such as [nephrin](https://bliptext.com/articles/nephrin), [podocin](https://bliptext.com/articles/podocin) and [CD2AP](https://bliptext.com/articles/cd2ap) allows this channel to be mechanosensitive, and hence TRPC6 channels can be activated by both chemical and mechanical stimuli.]]\n\n## In the central nervous system\nResearch 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.\nTRPC6 appears to be essential for the formation of an excitatory synapse; overexpressing TRPC6 greatly increased [dendritic spine](https://bliptext.com/articles/dendrite) density and the level of [synapsin I](https://bliptext.com/articles/synapsin-i) and [PSD-95 cluster](https://bliptext.com/articles/dlg4), known as the pre- and postsynaptic markers.\nTRPC6 has also been proven to participate in neuroprotection and its neuroprotective effect could be explained due to the antagonism of extrasynaptic [NMDA receptor](https://bliptext.com/articles/nmda-receptor) (NMDAR)-mediated intracellular calcium overload.\nTRPC6 activates [calcineurin](https://bliptext.com/articles/calcineurin), which impedes the NMDAR activity.\nHyperactivation of NMDAR is a critical event in [glutamate](https://bliptext.com/articles/glutamate)-driven [excitotoxicity](https://bliptext.com/articles/excitotoxicity) that causes a rapid increase in intracellular calcium concentration.\nSuch rapid increases in cytoplasmic calcium concentrations may activate and over-stimulate a variety of [proteases](https://bliptext.com/articles/proteases), [kinases](https://bliptext.com/articles/kinases), [endonucleases](https://bliptext.com/articles/endonucleases), etc. This downstream neurotoxic cascade may trigger severe damage to neuronal functioning.\nHyperactivation of NMDAR is frequently observed during [brain ischemia](https://bliptext.com/articles/brain-ischemia) and late stage [Alzheimer's disease](https://bliptext.com/articles/alzheimer-s-disease).\n\n# Clinical significance\nSince 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:\n

Kidney diseases• Proteinuria\n• Focal segmental glomerulosclerosis\n• Diabetic nephropathy

Disorders of the nervous system• Alzheimer's disease\n• Autism spectrum disorders\n• Brain ischemia

Cancers• Breast cancer\n• Esophageal cancer\n• Lung cancer\n• Liver cancer\n• Renal cell carcinoma

Cardiovascular diseases• Heart failure\n• Hypertrophic cardiomyopathy\n• Coronary artery disease

Pulmonary diseases• Pulmonary hypertension\n• COVID-19\n• Airway inflammation\n• Chronic obstructive pulmonary disease\n• Lung fibrosis

\n\n\n# Interactions\nTRPC6 has been shown to [interact](https://bliptext.com/articles/protein-protein-interaction) with:\n\n# Ligands\nTwo of the primary [active constituents](https://bliptext.com/articles/active-constituent) responsible for the [antidepressant](https://bliptext.com/articles/antidepressant) and [anxiolytic](https://bliptext.com/articles/anxiolytic) [benefits](https://bliptext.com/articles/therapeutic-effect) of [Hypericum perforatum](https://bliptext.com/articles/hypericum-perforatum), also known as St. John's Wort, are [hyperforin](https://bliptext.com/articles/hyperforin) and ad[hyperforin](https://bliptext.com/articles/hyperforin).\nThese compounds are [inhibitors](https://bliptext.com/articles/[reuptake](https://bliptext.com/articles/reuptake)-inhibitor) of the [reuptake](https://bliptext.com/articles/reuptake) of [serotonin](https://bliptext.com/articles/serotonin), [norepinephrine](https://bliptext.com/articles/norepinephrine), [dopamine](https://bliptext.com/articles/dopamine), [γ-aminobutyric acid](https://bliptext.com/articles/aminobutyric-acid), and [glutamate](https://bliptext.com/articles/glutamate), and they are reported to exert these [effects](https://bliptext.com/articles/drug-action) by [binding](https://bliptext.com/articles/binding-molecular) to and [activating](https://bliptext.com/articles/receptor-theory) TRPC6.\nRecent results with hyperforin have cast doubt on these findings as similar currents are seen upon Hyperforin treatment regardless of the presence of TRPC6.","current_revision":null,"created_by":"kACnuQmH5k9Nr5VNVEpVeg7XpvUmMctD","created_at":"2025-01-26T09:43:33.235Z","updated_at":"2025-01-26T09:43:33.235Z","search_vector":"'trpc6':1","search_content":" \n \n\n# \n**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](https://bliptext.com/articles/gene).\n[TRPC](https://bliptext.com/articles/trpc)6 is a [transient receptor potential channel](https://bliptext.com/articles/transient-receptor-potential-channel) of the classical [TRPC](https://bliptext.com/articles/trpc) subfamily.\nTRPC6 channels are **nonselective** [cation channels](https://bliptext.com/articles/cation-channel-superfamily) that respond directly to [diacylglycerol](https://bliptext.com/articles/diglyceride) (DAG), a product of [phospholipase C](https://bliptext.com/articles/phospholipase-c) activity.\nThis activation leads to cellular [depolarization](https://bliptext.com/articles/depolarization) and [calcium](https://bliptext.com/articles/calcium) influx.\nUnlike the closely related [TRPC3](https://bliptext.com/articles/trpc3) channels, TRPC6 channels possess the distinctive ability to transport [heavy metal](https://bliptext.com/articles/heavy-metals) ions.\nTRPC6 channels facilitate the transport of [zinc](https://bliptext.com/articles/zinc) ions, promoting their accumulation inside cells.\nIn addition, despite their non-selectiveness, TRPC6 exhibits a strong preference for calcium ions, with a permeability ratio of calcium to sodium (/) of roughly six.\nThis selectivity is significantly higher compared to TRPC3, which displays a weaker preference for calcium with a (/) ratio of only 1.1.\n\n# Function\n**TRPC6 channels are widely distributed in the human body and are emerging as crucial regulators of several key physiological functions:**\n\n## In blood vessels\nSmall arteries and [arterioles](https://bliptext.com/articles/arterioles) exhibit a self-regulatory mechanism called [myogenic tone](https://bliptext.com/articles/myogenic-mechanism), enabling them to maintain relatively stable blood flow despite fluctuating [intravascular pressures](https://bliptext.com/articles/blood-pressure).\nWhen intravascular pressure within a small artery or arteriole increases, the vessel walls automatically [constrict](https://bliptext.com/articles/vasoconstriction).\nThis narrowing reduces blood flow, effectively counteracting the rising pressure and stabilizing overall flow.\nConversely, if blood pressure suddenly drops, [vasodilation](https://bliptext.com/articles/vasodilation) occurs to allow more blood flow and compensate for the decrease.\nTRPC6 channels are present both in [endothelial](https://bliptext.com/articles/endothelium) and [smooth muscle](https://bliptext.com/articles/smooth-muscle) cells, and their function is similar to [α‑adrenoreceptors](https://bliptext.com/articles/alpha-1-adrenergic-receptor); they are both involved in vasoconstriction.\nHowever, TPRC6-mediated vasoconstriction is [mechanosensetive](https://bliptext.com/articles/mechanosensitive-channels) (i.e. activated by mechanical stimulation) and these channels are involved in maintenance of the [myogenic tone](https://bliptext.com/articles/myogenic-mechanism) of blood vessels and autoregulation of blood flow.\nWhen intravascular blood pressure rises, this causes stretching of the walls of blood vessels.\nThis mechanical stretch activates the TRPC6 channel.\nOnce activated, TRPC6 allows Ca2+ to enter the smooth muscle cells.\nThis increase in intracellular Ca2+ triggers [a chain reaction](https://bliptext.com/articles/vasoconstriction) leading to vasoconstriction.\n\n## In the kidneys\nTRPC6 channels are extensively present throughout the kidney, both in the [tubular segments](https://bliptext.com/articles/nephron) and the [glomeruli](https://bliptext.com/articles/glomerulus-kidney).\nWithin the glomeruli, expression of TRPC6 is primarily concentrated in [podocytes](https://bliptext.com/articles/podocytes).\nDespite 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.\nPodocytes normally display minimal baseline activity of TRPC6 channels and TRPC6 [knockout mice](https://bliptext.com/articles/knockout-mouse) have not shown any evident changes in glomerular structure or filtration.\nNevertheless, it has been hypothesized that the function of TRPC6 channels in podocytes resembles their function in smooth muscles of blood vessels.\nGlomerular capillaries operate under significantly higher pressure than most other capillary beds.\nWhen podocytes are stretched by glomerular capillary pressure, mechanosensitive TRPC6 channels trigger a surge in Ca2+ influx into podocytes, causing them to contract.\nThis podocyte contraction exerts a force that opposes capillary wall overstretching and distention, that would otherwise lead to protein leakage.\nHowever, 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](https://bliptext.com/articles/bk-channel), leading to the efflux of K+.\nBK 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.\nTRPCandBK.jpg (Ang II) activates [phospholipase C](https://bliptext.com/articles/phospholipase-c) (PLC), which cleaves [phosphatidylinositol 4,5-bisphosphate](https://bliptext.com/articles/phosphatidylinositol-4-5-bisphosphate) (PIP2) into [diacyl glycerol](https://bliptext.com/articles/diacyl-glycerol) (DAG) and [inositol 1,4,5-trisphosphate](https://bliptext.com/articles/inositol-1-4-5-trisphosphate) (IP3). DAG activates TRPC6 channels, and IP3 binds to its receptor on the [endoplasmic reticulum](https://bliptext.com/articles/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.\nThe upper side of the figure illustrates that TRPC6 interaction with podocyte-specific proteins such as [nephrin](https://bliptext.com/articles/nephrin), [podocin](https://bliptext.com/articles/podocin) and [CD2AP](https://bliptext.com/articles/cd2ap) allows this channel to be mechanosensitive, and hence TRPC6 channels can be activated by both chemical and mechanical stimuli.]]\n\n## In the central nervous system\nResearch 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.\nTRPC6 appears to be essential for the formation of an excitatory synapse; overexpressing TRPC6 greatly increased [dendritic spine](https://bliptext.com/articles/dendrite) density and the level of [synapsin I](https://bliptext.com/articles/synapsin-i) and [PSD-95 cluster](https://bliptext.com/articles/dlg4), known as the pre- and postsynaptic markers.\nTRPC6 has also been proven to participate in neuroprotection and its neuroprotective effect could be explained due to the antagonism of extrasynaptic [NMDA receptor](https://bliptext.com/articles/nmda-receptor) (NMDAR)-mediated intracellular calcium overload.\nTRPC6 activates [calcineurin](https://bliptext.com/articles/calcineurin), which impedes the NMDAR activity.\nHyperactivation of NMDAR is a critical event in [glutamate](https://bliptext.com/articles/glutamate)-driven [excitotoxicity](https://bliptext.com/articles/excitotoxicity) that causes a rapid increase in intracellular calcium concentration.\nSuch rapid increases in cytoplasmic calcium concentrations may activate and over-stimulate a variety of [proteases](https://bliptext.com/articles/proteases), [kinases](https://bliptext.com/articles/kinases), [endonucleases](https://bliptext.com/articles/endonucleases), etc. This downstream neurotoxic cascade may trigger severe damage to neuronal functioning.\nHyperactivation of NMDAR is frequently observed during [brain ischemia](https://bliptext.com/articles/brain-ischemia) and late stage [Alzheimer's disease](https://bliptext.com/articles/alzheimer-s-disease).\n\n# Clinical significance\nSince 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:\n Kidney diseases• Proteinuria\n• Focal segmental glomerulosclerosis\n• Diabetic nephropathy \n Disorders of the nervous system• Alzheimer's disease\n• Autism spectrum disorders\n• Brain ischemia \n Cancers• Breast cancer\n• Esophageal cancer\n• Lung cancer\n• Liver cancer\n• Renal cell carcinoma \n Cardiovascular diseases• Heart failure\n• Hypertrophic cardiomyopathy\n• Coronary artery disease \n Pulmonary diseases• Pulmonary hypertension\n• COVID-19\n• Airway inflammation\n• Chronic obstructive pulmonary disease\n• Lung fibrosis \n \n\n# Interactions\nTRPC6 has been shown to [interact](https://bliptext.com/articles/protein-protein-interaction) with:\n\n# Ligands\nTwo of the primary [active constituents](https://bliptext.com/articles/active-constituent) responsible for the [antidepressant](https://bliptext.com/articles/antidepressant) and [anxiolytic](https://bliptext.com/articles/anxiolytic) [benefits](https://bliptext.com/articles/therapeutic-effect) of [Hypericum perforatum](https://bliptext.com/articles/hypericum-perforatum), also known as St. John's Wort, are [hyperforin](https://bliptext.com/articles/hyperforin) and ad[hyperforin](https://bliptext.com/articles/hyperforin).\nThese compounds are [inhibitors](https://bliptext.com/articles/[reuptake](https://bliptext.com/articles/reuptake)-inhibitor) of the [reuptake](https://bliptext.com/articles/reuptake) of [serotonin](https://bliptext.com/articles/serotonin), [norepinephrine](https://bliptext.com/articles/norepinephrine), [dopamine](https://bliptext.com/articles/dopamine), [γ-aminobutyric acid](https://bliptext.com/articles/aminobutyric-acid), and [glutamate](https://bliptext.com/articles/glutamate), and they are reported to exert these [effects](https://bliptext.com/articles/drug-action) by [binding](https://bliptext.com/articles/binding-molecular) to and [activating](https://bliptext.com/articles/receptor-theory) TRPC6.\nRecent results with hyperforin have cast doubt on these findings as similar currents are seen upon Hyperforin treatment regardless of the presence of TRPC6.","revisionCount":0},"hasMore":false,"nextCursor":null}

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