Valdecoxib blocks rat TRPV2 channels.

The transient receptor potential vanilloid 2 (TRPV2) channel is broadly expressed in a multitude of different tissues and is implicated in the pathology of several diseases, such as the progression of different cancer types. However, a lack of specific, potent and non-toxic TRPV2 activators and inhibitors complicate further studies to clarify the role of TRPV2. We here present valdecoxib as a novel inhibitor of heterologously expressed rat TRPV2 channels in HEK293 cells and native TRPV2 channels, endogenously expressed in the rat basophilic leukemia (RBL-2H3) cell line. Fluorometric assays reveal an IC50 of 9 μM and 11 μM for TRPV2 in HEK293 and RBL-2H3 cells, respectively. Closely related TRPV1, TRPV3 or TRPV4 channels are not blocked by valdecoxib. The inhibition is reversible and direct as confirmed by whole-cell and excised inside-out electrophysiological recordings. Other cyclooxygenase-2 inhibitors do not affect TRPV2 activity. Furthermore, we demonstrate that the combined application of 2-aminoethoxydiphenyl borate (2-APB) and probenecid at concentrations, which, on their own, elicit only small TRPV2 currents, act in a highly synergistic manner when applied simultaneously. Taken together, we here provide novel tools and chemical lead structures for further studying TRPV2 channel function in native tissues.