Dynamics of receptor-operated Ca2+ currents through TRPC channels controlled via the PI(4,5),P2-PLC signaling pathway

Transient receptor potential canonical (TRPC) channels are Ca2+-permeable, nonselective cation channels that carry receptor-operated Ca2+ currents (ROCs) triggered by receptor-induced, phospholipase C (PLC)-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P-2]. Within the vasculature, TRPC channel ROCs contribute to smooth muscle cell depolarization, vasoconstriction, and vascular remodeling. However, TRPC channel ROCs exhibit a variable response to receptor-stimulation, and the regulatory mechanisms governing TRPC channel activity remain obscure. The variability of ROCs may be explained by their complex regulation by PI(4,5)P-2 and its metabolites, which differentially affect TRPC channel activity. To resolve the complex regulation of ROCs, the use of voltage-sensing phosphoinositide phosphatases and model simulation have helped to reveal the time-dependent contribution of PI(4,5)P-2 and the possible role of PI(4,5)P-2 in the regulation of ROCs. These approaches may provide unprecedented insight into the dynamics of PI(4,5)P-2 regulation of TRPC channels and the fundamental mechanisms underlying transmembrane ion flow. Within that context, we summarize the regulation of TRPC channels and their coupling to receptor-mediated signaling, as well as the application of voltage-sensing phosphoinositide phosphatases to this research. We also discuss the controversial bidirectional effects of PI(4,5)P-2 using a model simulation that could explain the complicated effects of PI(4,5)P-2 on different ROCs.