Polymodal TRPC signaling: Emerging role in phenotype switching and tissue remodeling

TRPC proteins have been implicated in a large array of Ca(2+) signaling processes and are considered as pore-forming subunits of unique polymodal channel sensors. The mechanisms of TRPC activation are so far incompletely understood but appear to involve a concert of signals that are generated typically downstream of receptor-mediated activation of phospholipase C. Specifically for the TRPC1/4/5 subfamily the activating scenario is ill-defined and appears enigmatic due to the observation of multiple modes of activation. TRPC4 was initially described as a store-operated cation channel and was repeatedly proposed as a pivotal element of the store-operated signaling pathways of various tissues. However, classical reconstitution of TRPC4 complexes in expression systems as well as recent knock-down strategies provided evidence against store-dependent regulation of this channel and raised considerable doubt in its proposed prominent role agonist-induced Ca(2+) signaling. Recent analysis of the function of TRPC4 in vascular endothelial cells of divergent phenotype revealed a novel aspect of TRPC signaling, extending the current concept of TRPC regulation by a phenotype-dependent switch between Ca(2+) transport and a potential intracellular scaffold function of the TRPC protein.