TRPC Channels

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 G_q/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 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 :

• IUPHAR Receptor Code

• BJP Guide

TRPC Gene Data