Journal
FRONTIERS IN PHARMACOLOGY
Volume 6, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2015.00022
Keywords
receptor-operated calcium current; TRPC channels; PIP2; voltage-sensing phosphatase; Ca2+ signaling; smooth muscle
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Funding
- Japan Society for the Promotion of Sciences
- Grants-in-Aid for Scientific Research [22136001, 26840032, 15H04678] Funding Source: KAKEN
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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.
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