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Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives Watanabe H; Davis JB; Smart D; Jerman JC; Smith GD; Hayes P; Vriens J; Cairns W; Wissenbach U; Prenen J; Flockerzi V; Droogmans G; Benham CD; Nilius BJ Biol Chem 2002[Apr]; 277 (16): 13569-77We have studied activation by phorbol derivatives of TRPV4 channels, the human VRL-2, and murine TRP12 channels, which are highly homologous to the human VR-OAC, and the human and murine OTRPC4 channel. 4alpha-Phorbol 12,13-didecanoate (4alpha-PDD) induced an increase in intracellular Ca(2+) concentration, [Ca(2+)](i), in 1321N1 cells stably transfected with human VRL-2 (hVRL-2.1321N1) or HEK-293 cells transiently transfected with murine TRP12, but not in nontransfected or mock-transfected cells. Concomitantly with the increase in [Ca(2+)](i), 4alpha-PDD activated an outwardly rectifying cation channel with an Eisenman IV permeation sequence for monovalent cations that is Ca(2+)-permeable with P(Ca)/P(Na) = 5.8. Phorbol 12-myristate 13-acetate also induced an increase in [Ca(2+)](i) but was approximately 50 times less effective than 4alpha-PDD. EC(50) for Ca(2+) increase and current activation was nearly identical (pEC(50) approximately 6.7). Similar effects were observed in freshly isolated mouse aorta endothelial cells which express TRP12 endogenously. By using 4alpha-PDD as a tool to stimulate TRP12, we showed that activation of this channel is modulated by [Ca(2+)](i); an increase in [Ca(2+)](i) inhibits the channel with an IC(50) of 406 nm. Ruthenium Red at a concentration of 1 microm completely blocks inward currents at -80 mV but has a smaller effect on outward currents likely indicating a voltage dependent channel block. We concluded that the phorbol derivatives activate TRPV4 (VR-OAC, VRL-2, OTRPC4, TRP12) independently from protein kinase C, in a manner consistent with direct agonist gating of the channel.|*Cation Transport Proteins[MESH]|Animals[MESH]|Calcium/metabolism[MESH]|Cell Line[MESH]|Cells, Cultured[MESH]|Coloring Agents/pharmacology[MESH]|Dose-Response Relationship, Drug[MESH]|Electrophysiology[MESH]|Endothelium, Vascular/metabolism[MESH]|Humans[MESH]|Ion Channels/agonists/*chemistry/*metabolism[MESH]|Kinetics[MESH]|Mice[MESH]|Phorbols/*pharmacology[MESH]|Receptors, Drug/agonists/*chemistry/*metabolism[MESH]|Recombinant Proteins/metabolism[MESH]|Ruthenium Red/pharmacology[MESH]|TRPV Cation Channels[MESH]|Transfection[MESH]|Tumor Cells, Cultured[MESH] |
