Abstract
Twenty-five years ago, the first mammalian Transient Receptor Potential Canonical (TRPC) channel was cloned, opening the vast horizon of the TRPC field. Today, we know that there are seven TRPC channels (TRPC1–7). TRPCs exhibit the highest protein sequence similarity to the Drosophila melanogaster TRP channels. Similar to Drosophila TRPs, TRPCs are localized to the plasma membrane and are activated in a G-protein-coupled receptor-phospholipase C-dependent manner. TRPCs may also be stimulated in a store-operated manner, via receptor tyrosine kinases, or by lysophospholipids, hypoosmotic solutions, and mechanical stimuli. Activated TRPCs allow the influx of Ca2+ and monovalent alkali cations into the cytosol of cells, leading to cell depolarization and rising intracellular Ca2+ concentration. TRPCs are involved in the continually growing number of cell functions. Furthermore, mutations in the TRPC6 gene are associated with hereditary diseases, such as focal segmental glomerulosclerosis. The most important recent breakthrough in TRPC research was the solving of cryo-EM structures of TRPC3, TRPC4, TRPC5, and TRPC6. These structural data shed light on the molecular mechanisms underlying TRPCs’ functional properties and propelled the development of new modulators of the channels. This review provides a historical overview of the major advances in the TRPC field focusing on the role of gene knockouts and pharmacological tools.
Highlights
Introduction and Historical OverviewThe term “TRP” (Transient Receptor Potential) was coined by Minke, Wu, and Pak in 1975 [1] and referred to a spontaneous Drosophila melanogaster mutant isolated by Cosens and Manning in 1969 [2]
These findings suggest a higher resistance of TRPC1/4/5/6 KO mice to diabetic retinopathy [207]
Tsvilovskyy et al concluded that TRPC4 and TRPC6 channel activation are critical for stimulating the muscarinic cation current in intestinal smooth muscle [255,256], indicating that the mICAT may consist of TRPC4 and TRPC6 and that their activation may be important for accelerating intestinal motility
Summary
The term “TRP” (Transient Receptor Potential) was coined by Minke, Wu, and Pak in 1975 [1] and referred to a spontaneous Drosophila melanogaster (fruit fly) mutant isolated by Cosens and Manning in 1969 [2]. Further evidence supporting the fact that TRPL forms a channel was provided in 1996 when the Günter Schultz laboratory published the recordings of single-channel activity of the TRPL channel induced by the purified Gq protein stimulating phospholipase C (PLC) in isolated inside-out patches [10]. In 1991, Minke and Selinger applied the Putney capacitative model to the TRP field, proposing that store-depletion might be involved in regulating TRP protein activity [18] Since this hypothesis has been attracting much interest in the Drosophila TRP field, with some studies supporting it [19,20], and others contesting it [21]. The Montell group provided evidence that the endogenous dTRP can heteromerize with dTRPL to form store-operated channels [27], concluding that the light-activated current in Drosophila photoreceptor cells results from a combination of TRP homo- and TRP–TRPL heteromultimers
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