TRPC4 Activators

The chemical class TRPC4 Activators primarily includes molecules that modulate G-protein-coupled receptor (GPCR) signaling and intracellular calcium dynamics. The members of this class act by altering the activity of these pathways to influence TRPC4 function indirectly. For instance, Bradykinin, Carbachol, ATP, Angiotensin II, and GTPγS function by activating GPCRs which in turn stimulate PLC activity. The activation of PLC leads to the hydrolysis of PIP2 into IP3 and DAG, both of which are known to activate TRPC4 channels. In a different context, U-73122, although a PLC inhibitor, paradoxically influences TRPC4 by potentially increasing PIP2 availability.

In another mechanism of action, Thapsigargin, SKF-96365, and Ionomycin influence TRPC4 via modulating intracellular calcium dynamics. Thapsigargin depletes intracellular calcium stores, initiating store-operated calcium entry (SOCE) which can activate TRPC4. SKF-96365 activates TRPC4 by inhibiting both receptor-operated calcium channels (ROCs) and store-operated calcium channels (SOCs). Ionomycin, a calcium ionophore, increases intracellular calcium concentration, activating TRPC4 channels through a positive feedback mechanism. Lastly, 1-oleoyl-2-acetyl-sn-glycerol (OAG), a synthetic analogof DAG, and Phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC), can also activate TRPC4 channels. OAG mimics the action of DAG, a product of PLC-induced PIP2 hydrolysis, and activates TRPC4. PMA, on the other hand, activates PKC, which phosphorylates and activates TRPC4.