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Coincident intracellular calcium rise is essential for Gi/o‐mediated activation of TRPC4 (843.3)

TRPC4 is a member of the Canonical Transient Receptor Potential family of non‐selective cation channels. Na+ and Ca2+ influx through the active TRPC4 channel elicits membrane depolarization and intracellular Ca2+ signaling in various cell types including neurons, vascular endothelium and smooth muscle cells. It has been well‐established that homomeric TRPC4 channels are synergistically activated by co‐stimulation of two separate G protein pathways, Gq/11 and Gi/o. However, it remains unclear which step(s) or constituent(s) of the Gq/11 pathway is(are) essential for synergizing with Gi/o proteins to maximally activate TRPC4 channels. Using patch‐clamp recordings and fluorescence membrane potential measurements in HEK293 cells heterologously coexpressing mouse TRPC4β and Gi/o‐coupled µ opioid receptor, we have identified intracellular Ca2+ rise as the primary event associated with Gq/11 activation that synergizes with Gi/o stimulation to elicit maximal TRPC4 current. We also show that a signification portion of this effect is independent of calmodulin although Ca2+‐calmodulin can enhance channel activation. Our experiments demonstrate the contribution of phosphoinositide hydrolysis and IP3 receptors but rule them out as essential players. These findings argue for a critical role of intracellular Ca2+ rise in TRPC4 activation by Gi/o‐coupled receptors and illustrate the key requirements that support TRPC4 as a coincidence sensor of multiple signaling pathways.