TRPV4--The EET Is On

The transient receptor potential V4 (TRPV4) channel is highly expressed in endothelial cells where either heat or a synthetic ligand can activate it. Watanabe et al. have now identified an endogenous chemical activator that stimulates this calcium entry channel. The ligand, an epoxyeicosatrienoic acid called 5,6-EET, is a metabolite of arachidonic acid (AA), which, in turn, is a metabolite of an endocannabinoid called anandamide (AEA). AEA was previously identified as an activator of TRPV1, a related channel. By treating transfected cells that overexpressed TRPV4 with pharmacological agents that inhibited various stages of AEA metabolism, the authors found that TRPV4 facilitated calcium entry and current conductance in response to 5,6-EET. When endothelial cells isolated from mouse aorta were treated with 5,6-EET, intracellular calcium concentration increased in a manner that was inhibited by blocking TRPV4. AEA and EETs are well-known vasorelaxants, which suggests that TRPV4 could be a molecular target for drug development. TRPV4 is also expressed in the hypothalamus and could underlie the psychoactive effects of some endocannabinoids. H. Watanabe, J. Vriens, J. Prenen, G. Droogmans, T. Voets, B. Nilius, Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424 , 434-438 (2003). [Online Journal]