TRPC channels form the subfamily of channels in human most closely related to drosophila TRP channels. In terms of structure, this family possesses a number of similar characteristics. At the proximal C-terminus of this sub-family is a TRP box motif containing the invariant EWKFAR sequence and between 3 and 4 ankyrin repeats near the N-terminus. These channels are non-selectively permeable to cations, with a selectivity of calcium over sodium variable among the different members. Many of TRPC channel subunits are able to coassemble. The predominant TRPC channels in the mammalian brain are the TRPC 1,4 and 5 and they are densely expressed in corticolimbic brain regions, like the hippocampus, prefrontal cortex and lateral septum. The TRPC channels 1,4 and 5 functional group is activated by the metabotropic glutamate receptor group 1 agonist DHPG.
In general, TRPC channels can be activated by phospholipase C stimulation, with some members also activated by diacylglycerol. There is one at least one report that TRPC1 is also activated by stretching of the membrane and TRPC5 channels are activated by extracellular reduced thioredoxin.
It has long been proposed that TRPC channels underlie the store-operated channels (SOC) observed in many cell types. These channels open due to the depletion of intracellular calcium stores. Two other proteins, stromal interaction molecules (STIMs) and the ORAIs, however, have more recently been implicated in this process. STIM1 and TRPC1 can coassemble, complicating the understanding of this phenomenon.
Role in cardiomyopathies
Research on the role of TRPC channels in cardiomyopathies is still in progress. An upregulation of TRPC1, TRPC3, and TRPC6 genes are seen in heart disease states including fibroblast formation and cardiovascular 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.
TRPC1 channels are activated by receptors coupled to phospholipase C (PLC), mechanical stimulation, and depletion of intracellular calcium stores. TRPC1 channels are found on cardiomyocytes, smooth muscle, and endothelial cells. Upon stimulation of these channels in cardiovascular disease, there is an increase in hypertension and cardiac hypertrophy. 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.
TRPC3 and TRPC6 channels are activated by PLC stimulation and diacylglycerol (DAG) production. 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 with atrial fibrillation (AF). TRPC3 regulates angiotensin II-induced cardiac hypertrophy which contributes to the formation of fibroblasts. Accumulation of fibroblasts in the heart can manifest into AF. Experiments blocking TRPC3 show a decrease in fibroblast formation and reduced AF susceptibility.
TRPC1, TRPC3, and TRPC6 channels are all involved in cardiac hypertrophy. The mechanism of how TRPC channels promote cardiac hypertrophy is through activation of the calcineurin pathway and the downstream transcription factor nuclear factor of activated T-cells (NFAT).
Pathological stress or hypertrophic agonists will trigger G-protein coupled receptors (GPCRs) and activates PLC to form DAG and inositol triphosphate (IP3). 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. NFAT translocate into the nucleus and induce gene transcription of more TRPC genes. This creates a positive feedback loop, leading to a state of hypertrophic gene expression and thus, cardiac growth and remodelling of the heart. TRPC channel's involvement in well studied signaling pathways and significance in gene impact on human diseases make it a potential target for drug therapy. TRPC has been shown to potentiate inhibition in the olfactory bulb circuit, providing a mechanism for improving olfactory abilities.
- Nilius B, Owsianik G, Voets T, Peters JA (2007). "Transient receptor potential cation channels in disease". Physiol. Rev. 87 (1): 165–217. doi:10.1152/physrev.00021.2006. PMID 17237345.
- Fowler, MA; Sidiropoulou, K; Ozkan, ED; Phillips, CW; Cooper, DC (2007). "Corticolimbic Expression of TRPC4 and TRPC5 Channels in the Rodent Brain". PLoS ONE. 2 (6): e573. doi:10.1371/journal.pone.0000573. PMC 1892805
. PMID 17593972.
- Fowler, M; Varnell, A; Dietrich, A.; Birnbaumer, L.; Cooper, DC. (2012). "Deletion of the trpc1 gene and the effects on locomotor and conditioned place-preference responses to cocaine". Nature Precedings. doi:10.1038/npre.2012.7153.1.
S. Z. Xu; P. Sukumar; F. Zeng; et al. (2008). "TRPC channel activation by extracellular thioredoxin". Nature. 451 (7174): 69–72. doi:10.1038/nature06414. PMC 2645077
. PMID 18172497.
- Boulay G, Brown DM, Qin N, et al. (December 1999). "Modulation of Ca(2+) entry by polypeptides of the inositol 1,4, 5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion-activated Ca(2+) entry". Proc. Natl. Acad. Sci. U.S.A. 96 (26): 14955–60. doi:10.1073/pnas.96.26.14955. PMC 24754
. PMID 10611319.
- Lessard CB; Lussier MP; Cayouette S; Bourque G; Boulay G. (2005). "The overexpression of presenilin2 and Alzheimer's-disease-linked presenilin2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells". Cell Signal. 17 (4): 437–445. doi:10.1016/j.cellsig.2004.09.005. PMID 15601622.
- Rowell, J.; Koitabashi, N.; Kass, D. (2010). "TRP-ing up heart and vessels: canonical transient receptor potentials and cardiovascular disease". Journal of Cardiovascular Translational Research. 3 (5): 516–524. doi:10.1007/s12265-010-9208-4. PMC 3875464
. PMID 20652467.
- Yue, Z.; Zhang, Y.; Xie, J.; Jiang, J.; Yue, L. (2013). "Transient receptor potential (TRP) channels and cardiac fibrosis". Current Topics in Medicinal Chemistry. 13 (3): 270–282. doi:10.2174/1568026611313030005. PMC 3874073
. PMID 23432060.
- Bush, E.; Hood, D.; Papst, P.; et al. (2006). "Mechanisms of signal transduction: canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling". The Journal of Biological Chemistry. 281 (44): 33487–33496. doi:10.1074/jbc.M605536200. PMID 16950785.
- 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. PMID 21804597.
- Smith, Richard (2009). "Excitatory actions of noradrenaline and metabotropic glutamate receptor activation in granule cells of the accessory olfactory bulb". Journal of Neurophysiology. 102: 1103–1114. doi:10.1152/jn.91093.2008. PMC 2724365
. PMID 19474170.
- TRPC+Cation+Channels at the US National Library of Medicine Medical Subject Headings (MeSH)
- "Transient Receptor Potential Channels". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- "TRIP Database". a manually curated database of protein-protein interactions for mammalian TRP channels.