TRPC Channels

TRPC channels (classical/canonical transient receptor potential channels) are the subfamily of TRPC channels most closely related to the first member of the TRP family to be discovered, the Drosophila TRP channel. There are seven family members (TRPC1 to TRPC7), although TRPC2 is not expressed in humans. TRPC channels are non-selective cation channels that are activated by the phospholipase C (PLC) signaling pathway, and they are linked to multiple physiological processes, such as neurotransmission, neurodevelopment, calcium signaling, kidney function, cardiovascular function, and immune response.

Products
Background
Gene Data

TRPC Channel Modulators

Cat. No. Product Name / Activity
6875 TRPC6-PAM-C20
Selective positive allosteric modulator (PAM) of TRPC6

TRPC Channel Inhibitors

Cat. No. Product Name / Activity
6766 AC 1903
Selective TRPC5 inhibitor
6495 AM 12
TRPC5 inhibitor
6494 Galangin
TRPC5 inhibitor; also induces autophagy
4912 GsMTx4
TRPC1 and TRPC6 inhibitor; inhibits mechanosensitive ion channels
7170 D-GsMTx4
TRPC1/6 and Piezo2 inhibitor; resistant to proteolytic digestion
5807 M 084 hydrochloride
TRPC4 and TRPC5 inhibitor; antidepressant and anxiolytic
4732 ML 204
Selective TRPC4 inhibitor
6941 Pyr 10
Selective TRPC3 inhibitor
3751 Pyr3
Selective TRPC3 inhibitor
5831 SAR 7334
Potent TRPC6 inhibitor
1147 SKF 96365 hydrochloride
TRPC channel inhibitor; also inhibits store-operated Ca2+ entry

TRPC Channel Activators

Cat. No. Product Name / Activity
6940 BTD
Selective TRPC5 activator
4522 Flufenamic acid
Activates TRPC6; NSAID
6508 GSK 1702934A
Potent and selective TRPC3/6 activator
0768 Riluzole hydrochloride
TRPC5 activator; also inhibits GABA uptake and glutamate release and blocks NaV channels

Other

Cat. No. Product Name / Activity
7013 OptoBI-1
Photoswitchable TRPC3/6/7 agonist

TRPC channels are complexes formed by four subunits, each with 6-transmembrane domains and several common features such as 3 or 4 ankyrin repeats in the N-terminal and a TRP box motif at proximal C-terminal. These cation channels are activated, to varying extents, by phospholipase C signaling pathway components, downstream of Gq/11 G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). Activation of TRPC channels leads to cation influx, membrane depolarization and elevation of intracellular Ca2+. Endogenous TRPC channels can be homomeric or heteromeric, with some subunits preferentially associating with other specific subunits. For example, TRPC1 subunits do not form homomers, but are thought to act as a modulatory subunit within TRPC4 or TRPC5-containing channels.

TRPC2 is a pseudogene in humans, meaning it is not expressed. The functional protein is found in other mammals, including rats and mice, where it is located in the microvilli of vomeronasal organ, and is required for normal sexual behaviour in response to pheromones.

TRPC channels are expressed in a wide array of tissue and cell types, and so are implicated in a diverse range of physiological and disease processes, including but not limited to cardiovascular remodeling, atrial fibrillation, angiogenesis, lung function and respiratory diseases, kidney diseases, salivary gland function, inflammation and immune response, neurotransmission, neurodevelopment, neurodegeneration and stroke.

TRPC Channel Reported Expression, and Endogenous Activators and Modulators

TRPC Channel Reported Expression Example Stimuli & Modulators
TRPC1 Corticolimbic regions of brain, cardiomyocytes, smooth muscle cells, endothelial cells NO-mediated S-nitrosylation; membrane stretch; La3+
TRPC2 (non-human) Microvilli in vomeronasal organ 1,2-diacylglycerol (DAG); Intracellular Ca2+
TRPC3 Pituitary gland, brain stem, mGluR1-expressing neurons DAG
TRPC4 Corticolimbic regions of brain, broad peripheral expression NO-mediated S-nitrosylation; La3+; intracellular Ca2+
TRPC5 Corticolimbic regions of brain, broad peripheral expression NO-mediated S-nitrosylation; extracellular H+; membrane stretch; intracellular Ca2+
TRPC6 Multiple brain areas, heart, lung, pancreas, kidney DAG; membrane stretch
TRPC7 Heart, lung, kidneys and brain DAG


TRPC Channel Activation Mechanisms

Multiple components of the phospholipase C signaling pathway modulate TRPC channels. PLC catalyzes the cleavage of inositol 1,4,5-triphosphate (IP3) and DAG from phosphatidylinositol 4,5-biphosphate (PIP2), both of which can activate TRPC channels. DAG directly activates all TRPC channel family members, while IP3 positively modulates TRPC7 channels only. IP3 receptors are reported to be physically associated with TRPC channels via direct binding of the IP3 receptor N-terminal to a CIRB motif located in the TRPC channel C-terminal. Endogenous TRPC1, TRPC3 and TRPC4-containing channels are activated by IP3 receptors, but are inhibited by calmodulin binding, which completes with IP3 receptors for binding to the CIRB motif. PIP2, and H+ produced by the hydrolysis of PIP2 also modulate TRPC channels.

Changes in intracellular Ca2+ levels can have both positive and negative modulatory effects on TRPC channels, depending on the signaling mechanism that links Ca2+ to TRPC channels. A diverse range of mechanisms achieve this, including direct Ca2+ binding, activation of calmodulin or calmodulin-dependent kinase II (CaMKII), and vesicular trafficking. The sensitivity of a TRPC channel to Ca2+ modulation varies depending on TRPC subunit conformation. As TRPC channels are cation channels, their modulation by Ca2+ also leads to both positive and negative feedback loops.

Some research suggests that TRPC channels can function as store-operated calcium channels, meaning depletion of intracellular calcium stores results in their activation. However, conflicting reports also show they are insensitive to store depletion. More recently, STIM1-Orai channels have been implicated sensing intracellular Ca2+ store depletion, with STIM1 acting to sense depletion in the endoplasmic reticulum, which then activates Orai1, a transmembrane Ca2+ release activated Ca2+ (CRAC) channel.

TRPC Inhibitors in Disease

TRPC inhibitors have been investigated for their efficacy in a variety of diseases. For example, Pyr 3 (Cat. No. 3751), a TRPC3 inhibitor has been examined for its efficacy in cardiovascular disorders such as cardiac hypertrophy and atrial remodeling. However, it also inhibits Orai1 with equal potency; its structural analog Pyr 10 (Cat. No. 6941) displays 10-fold higher selectivity for TRPC3 channels. SAR 7334 (Cat. No. 5831), a potent TRPC6 inhibitor prevents acute hypoxic pulmonary vasoconstriction, and protects renal proximal tubular cells from oxidative stress-induced apoptosis. In various animal models of pain, ML 204 (Cat. No. 4732), a TRPC4 and TRPC5 inhibitor, displays analgesic effects. Similarly, the TRPC4 and TRPC5 inhibitor M 084 (Cat. No. 5807) displays antidepressant and anxiolytic effects in animal models. In relation to cancer, SKF 96365 (Cat. No. 1147), a non-selective TRPC inhibitor exerts cytotoxic effects in multiple cancer cells lines, inducing cell cycle arrest at G2/M phase.

External sources of pharmacological information for TRPC Channels :

TRPC Gene Data

Gene Species Gene Symbol Gene Accession No. Protein Accession No.
TRPC, member 1 Human TRPC1 NM_003304 P48995
Mouse Trpc1 NM_011643 NP_035773
Rat Trpc1 NM_053558 NP_446010
TRPC, member 3 Human TRPC3 NM_003305 Q13507
Mouse Trpc3 NM_019510 NP_062383
Rat Trpc3 NM_021771 NP_068539
TRPC, member 4 Human TRPC4 NM_003306 Q9UBN4
Mouse Trpc4 NM_016984 NP_058680
Rat Trpc4 NM_001083115 NP_001076584
TRPC, member 5 Human TRPC5 NM_012471 Q9UL62
Mouse Trpc5 NM_009428 NP_033454
Rat Trpc5 NM_080898 NP_543174
TRPC, member 6 Human TRPC6 NM_004621 Q9Y210
Mouse Trpc6 NM_013838 NP_038866
Rat Trpc6 NM_053559 NP_446011
TRPC, member 7 Human TRPC7 NM_020389 Q9HCX4
Mouse Trpc7 NM_012035 NP_036165
Rat Trpc7 NM_001191691 NP_001178620