TRPC channels form the subfamily of channels in humans most closely related todrosophila TRP channels. Structurally, members of this family possess a number of similar characteristics, including 3 or 4ankyrin repeats near theN-terminus and a TRP box motif containing the invariant EWKFAR sequence at the proximal C-terminus. These channels are non-selectively permeable to cations, with a prevalence of calcium over sodium variable among the different members. Many of TRPC channel subunits are able to coassemble.[1]The predominant TRPC channels in the mammalianbrain are the TRPC 1,4 and 5 and they are densely expressed in corticolimbic brain regions, like thehippocampus,prefrontal cortex and lateral septum.[2][3] These 3 channels are activated by themetabotropic glutamate receptor 1 agonistdihydroxyphenylglycine.[2]
In general, TRPC channels can be activated byphospholipase C stimulation, with some members also activated bydiacylglycerol. There is at least one report that TRPC1 is also activated by stretching of the membrane and TRPC5 channels are activated by extracellular reducedthioredoxin.[4]
It has long been proposed that TRPC channels underlie thecalcium release activated channels observed in many cell types.[5] These channels open due to the depletion of intracellular calcium stores. Two other proteins, stromal interaction molecules (STIMs) and Orais, however, have more recently been implicated in this process.STIM1 andTRPC1 can coassemble, complicating the understanding of this phenomenon.[1]
TRPC6 has been implicated in late onset Alzheimer's disease.[6]
Research on the role of TRPC channels incardiomyopathies is still in progress. An upregulation ofTRPC1,TRPC3, andTRPC6 genes are seen in heart disease states includingfibroblast formation andcardiovascular disease. The TRPC channels are suspected of responding to an overload of hormonal and mechanical stimulation in cardiovascular disease, contributing to pathological remodelling of the heart.[7]
TRPC1 channels are activated by receptors coupled tophospholipase C (PLC), mechanical stimulation, and depletion of intracellular calcium stores. TRPC1 channels are found oncardiomyocytes,smooth muscle, andendothelial cells.[7] Upon stimulation of these channels in cardiovascular disease, there is an increase inhypertension and cardiachypertrophy.[7] TRPC1 channels mediate smooth muscle proliferation in the presence of pathological stimuli which contributes to hypertension. Mice with myocardial hypertrophy exhibit increased expression of TRPC1. The deletion of the TRPC1 gene in these mice resulted in reduced hypertrophy upon stimulation with hypertrophic stimuli, inferring that TRPC1 has a role in the progression of cardiac hypertrophy.[7]
TRPC3 and TRPC6 channels are activated by PLC stimulation anddiacylglycerol (DAG) production.[7] Both these TRPC channel types play a role in cardiac hypertrophy and vascular disease like TRPC1. In addition, TRPC3 is upregulated in the atria of patients withatrial fibrillation (AF).[8] TRPC3 regulatesangiotensin II-induced cardiac hypertrophy which contributes to the formation offibroblasts. Accumulation of fibroblasts in the heart can manifest into AF. Experiments blocking TRPC3 show a decrease in fibroblast formation and reduced AF susceptibility.[8]
TRPC1, TRPC3, and TRPC6 channels are all involved in cardiac hypertrophy. The mechanism of how TRPC channels promote cardiac hypertrophy is through activation of thecalcineurin pathway and the downstream transcription factornuclear factor of activated T-cells (NFAT).[9]
Pathological stress or hypertrophic agonists will triggerG-protein coupled receptors (GPCRs) and activates PLC to form DAG andinositol triphosphate (IP3).[9]IP3 promotes the release of internal calcium stores and the influx of calcium via TRPC. When intracellular calcium reaches a threshold, it will activate the calcineurin /NFAT pathway. DAG activates the calcineurin/NFAT pathway directly.[9]NFATtranslocate into the nucleus and induce gene transcription of more TRPC genes. This creates apositive feedback loop, leading to a state of hypertrophic gene expression and thus, cardiac growth and remodelling of the heart.[9]TRPC channel's involvement in well studied signaling pathways and significance in gene impact on human diseases make it a potential target fordrug therapy.[10] TRPC has been shown to potentiate inhibition in the olfactory bulb circuit, providing a mechanism for improving olfactory abilities.[11]
^Fowler, M; Varnell, A; Dietrich, A.; Birnbaumer, L.; Cooper, DC. (2012). "Deletion of thetrpc1 gene and the effects on locomotor and conditioned place-preference responses to cocaine".Nature Precedings.doi:10.1038/npre.2012.7153.1 (inactive 12 July 2025).{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)
^Moran, M.; McAlexander, M.; Biro, T.; Szallasi, A. (2011). "Transient receptor potential channels as therapeutic targets".Nature Reviews. Drug Discovery.10 (8):601–620.doi:10.1038/nrd3456.hdl:2437/112735.PMID21804597.S2CID8809131.
"Transient Receptor Potential Channels".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2021-10-25. Retrieved2008-12-17.
"TRIP Database".a manually curated database of protein-protein interactions for mammalian TRP channels.
