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

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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: ACA; Diacylglycerol; Diacylglycerol-Sensitive TRPC3/6/7 Channels; Drosophila; Eicosatetraynoic acid; G-protein-mediated stimulation; Inositol 1,4,5-trisphosphate; MLCK-inhibiting peptides; SFKF-96365; SKF-96365; TRPC; TRPC2; TRPC3; TRPC3/6/7 channels; TRPC6; TRPC7; arachidonic acids; bicyclic polyprenylated acylphloroglucinol derivate; calcium homeostasis; calcium receptor; calcium-permeable ion channels; cyclooxygenases; cytochrome P450; dopamine; gadolinium; gingival keratinocytes; hyperforin; inositol-trisphosphate; lanthanum; lipoxygenases; norepinephrine; pheromone signalling; phospholipase A2 inhibitor; phospholipase C; protein kinase C; serotonin; stromal interactions molecule; transient receptor potential channels; xestospongin C

Document Type: Research Article

Publication date: January 1, 2011

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  • Current Pharmaceutical Biotechnology aims to cover all the latest and outstanding developments in Pharmaceutical Biotechnology. Each issue of the journal contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics in both pre-clinical and clinical areas of Pharmaceutical Biotechnology. Current Pharmaceutical Biotechnology is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments.

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