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PKCalpha mediates acetylcholine-induced activation of TRPV4-dependent calcium influx in endothelial cells Adapala RK; Talasila PK; Bratz IN; Zhang DX; Suzuki M; Meszaros JG; Thodeti CKAm J Physiol Heart Circ Physiol 2011[Sep]; 301 (3): H757-65Transient receptor potential vanilloid channel 4 (TRPV4) is a polymodally activated nonselective cationic channel implicated in the regulation of vasodilation and hypertension. We and others have recently shown that cyclic stretch and shear stress activate TRPV4-mediated calcium influx in endothelial cells (EC). In addition to the mechanical forces, acetylcholine (ACh) was shown to activate TRPV4-mediated calcium influx in endothelial cells, which is important for nitric oxide-dependent vasodilation. However, the molecular mechanism through which ACh activates TRPV4 is not known. Here, we show that ACh-induced calcium influx and endothelial nitric oxide synthase (eNOS) phosphorylation but not calcium release from intracellular stores is inhibited by a specific TRPV4 antagonist, AB-159908. Importantly, activation of store-operated calcium influx was not altered in the TRPV4 null EC, suggesting that TRPV4-dependent calcium influx is mediated through a receptor-operated pathway. Furthermore, we found that ACh treatment activated protein kinase C (PKC) alpha, and inhibition of PKCalpha activity by the specific inhibitor Go-6976, or expression of a kinase-dead mutant of PKCalpha but not PKCepsilon or downregulation of PKCalpha expression by chronic 12-O-tetradecanoylphorbol-13-acetate treatment, completely abolished ACh-induced calcium influx. Finally, we found that ACh-induced vasodilation was inhibited by the PKCalpha inhibitor Go-6976 in small mesenteric arteries from wild-type mice, but not in TRPV4 null mice. Taken together, these findings demonstrate, for the first time, that a specific isoform of PKC, PKCalpha, mediates agonist-induced receptor-mediated TRPV4 activation in endothelial cells.|Acetylcholine/*pharmacology[MESH]|Animals[MESH]|Calcium Signaling/*drug effects[MESH]|Carbazoles/pharmacology[MESH]|Cells, Cultured[MESH]|Endothelial Cells/*drug effects/enzymology[MESH]|Enzyme Activation[MESH]|Male[MESH]|Mesenteric Arteries/drug effects/enzymology[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Mice, Knockout[MESH]|Mutation[MESH]|Nitric Oxide Synthase Type III/metabolism[MESH]|Phosphorylation[MESH]|Protein Kinase C-alpha/genetics/*metabolism[MESH]|Protein Kinase Inhibitors/pharmacology[MESH]|TRPV Cation Channels/*agonists/deficiency/genetics/metabolism[MESH]|Tetradecanoylphorbol Acetate/pharmacology[MESH]|Time Factors[MESH]|Transfection[MESH]|Vasodilation/*drug effects[MESH]|Vasodilator Agents/*pharmacology[MESH] |
