Pharmacological Modulation of Diacylglycerol-Sensitive TRPC3/6/7 Channels

Members of the classic type of transient receptor potential channels (TRPC) represent important molecules involved in hormonal signal transduction. TRPC3/6/7 channels are of particular interest as they are components of phospholipase C driven signalling pathways. Upon receptor-activation, G-protein-mediated stimulation of phospholipase C results in breakdown of phosphatidylinositides leading to increased intracellular diacylglycerol and inositol-trisphosphate levels. Diacylglycerol activates protein kinase C, but more interestingly diacylglycerol directly activates TRPC2/3/6/7 channels. Molecular cloning, expression and characterization of TRP channels enabled reassignment of traditional inhibitors of receptor-dependent calcium entry such as SKF-96365 and 2-APB as blockers of TRPC3/6/7 and several members of non-classic TRP channels. Furthermore, several enzyme inhibitors have also been identified as TRP channel blockers, such as ACA, a phospholipase A2 inhibitor, and W-7, a calmodulin antagonist. Finally, the naturally occurring secondary plant compound hyperforin has been identified as TRPC6-selective drug, providing an exciting proof of concept that it is possible to generate TRPC-selective channel modulators. The description of Pyr3 as the first TRPC3-selective inhibitor shows that not only nature but also man is able to generate TRP-selective modulators. The review sheds lights on the current knowledge and historical development of pharmacological modulators of TRPC3/6/7. Our analysis indicates that Pyr3 and hyperforin provide promising core structures for the development of new, selective and more potent modulators of TRPC3/6/7 activity. Keywords: Diacylglycerol, hyperforin, ACA, SFKF-96365, calcium homeostasis, Diacylglycerol-Sensitive TRPC3/6/7 Channels, transient receptor potential channels, TRPC, phospholipase C, TRPC3/6/7 channels, G-protein-mediated stimulation, inositol-trisphosphate, protein kinase C, SKF-96365, phospholipase A2 inhibitor, Inositol 1,4,5-trisphosphate, TRPC2, TRPC3, TRPC6, TRPC7, Drosophila, arachidonic acids, Eicosatetraynoic acid, lipoxygenases, cyclooxygenases, cytochrome P450, pheromone signalling, calcium-permeable ion channels, gadolinium, lanthanum, xestospongin C, stromal interactions molecule, MLCK-inhibiting peptides, bicyclic polyprenylated acylphloroglucinol derivate, serotonin, dopamine, norepinephrine, calcium receptor, gingival keratinocytes