Abstract
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)P2]. 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)P2 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)P2 and the possible role of PI(4,5)P2 in the regulation of ROCs. These approaches may provide unprecedented insight into the dynamics of PI(4,5)P2 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)P2 using a model simulation that could explain the complicated effects of PI(4,5)P2 on different ROCs.
Highlights
Calcium is a ubiquitous and fundamental messenger that triggers numerous downstream cellular events, including hormone secretion, vasoconstriction, and activity-dependent gene expression, to name a few (Berridge, 2012)
PHYSIOLOGICAL PATHWAY FOR receptor-operated Ca2+ currents (ROCs) OF transient receptor potential canonical (TRPC) CURRENTS Transient receptor potential canonical channels are widely distributed in various other tissues (Beech, 2013)
The effects of noradrenaline are mediated via activation of adrenergic receptors, including the α1A receptor, which is abundantly expressed on venous smooth muscle cells, and has been shown to induce ROCs through www.frontiersin.org
Summary
Calcium is a ubiquitous and fundamental messenger that triggers numerous downstream cellular events, including hormone secretion, vasoconstriction, and activity-dependent gene expression, to name a few (Berridge, 2012). It is known that in various vertebrate cell types ROCs are generated through the breakdown of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] by PLC upon receptor stimulation and are marked by Ca2+/Na+ ROCs has been studied in the Drosophila phototransduction pathway, wherein TRP channels mediate cation currents in response to photoreceptor activation (Hardie, 2011; Montell, 2011).
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