Stimulation of Transient Receptor Potential Channels TRPM3 and TRPM8 Increases Human Prostaglandin Endoperoxide Synthase-2 Promoter Activity

The transient receptor potential channels TRPM3 and TRPM8 are cation channels that regulate numerous cellular activities, including thermo- and pain sensation. Stimulation of either TRPM3 or TRPM8 channels induces an intracellular signaling cascade that leads to the activation of stimulus-responsive transcription factors. As part of a search for de-layed response genes activated upon TRPM3 or TRPM8 stimulation, we analyzed the gene encoding prostaglandin endoperoxide synthase-2. Expression of this gene is not detectable under basal conditions but is rapidly induced upon stimulation of the cells with numerous extracellular signaling molecules. Here, we show that chromatin-embedded reporter genes under the control of the prostaglandin endoperoxide synthase-2 promoter were activated after stimulation of TRPM3 with the steroid pregnenolone sulfate or TRPM8 channels with the super-cooling agent icilin. TRP channel-induced activation of the prostaglandin endoperoxide synthase-2 promoter was affected by pharmacological inhibitors of TRPM3 and TRPM8. Mutational analysis of the prostaglandin endoperoxide synthase-2 promoter showed the importance of a cAMP response element within the proximal promoter region of the prostaglandin endoperoxide synthase-2 gene. In summary, our results establish a link between the stimulation of TRPM3 and TRPM8 and the biosynthesis of proinflammatory mediators via the regulation of prostaglandin en-doperoxide synthase-2 expression.