The progesterone receptor regulates the expression of TRPV4 channel
The transient receptor potential cationic channel TRPV4 contributes to different aspects of cell physiology via the generation of a Ca2+ signal and/or depolarization of the membrane potential. TRPV4 channel integrates distinct physical and chemical stimuli, including osmotic and mechanical stress, heat, acidic pH, endogenous ligands, and synthetic agonists such as 4α-phorbol 12,13-didecanoate (4αPDD). Although several regulatory sites controlling TRPV4 channel activity have been identified, very little is known about the regulation of TRPV4 expression, a situation common to other TRP channels. Here we show that TRPV4 expression is under the control of progesterone in both human airways and mammary gland epithelial cells, as well as in vascular smooth muscle cells. Exposure of human airways epithelial CFT1-LCFSN and mammary gland epithelial T47D cells to progesterone decreased TRPV4 mRNA and protein expression. Consequently, 4αPDD-induced cationic currents and Ca2+ signals were also diminished in progesterone-treated cells. The effect of progesterone was reverted by the progesterone receptor (PR) antagonist RU-486 or following transfection with small interference RNA (siRNA) against both PRA and PRB isoforms. Interestingly, TRPV4 expression and activity were increased in T47D mammary gland epithelial cells when PR was silenced with siRNA. Transcriptional regulation of −1.3 kB TRPV4 promoter-luciferase plasmids was also evaluated in vascular smooth muscle cells. TRPV4 promoter activity was reduced by coexpression with PR and further reduced in the presence of PG. Together, our data report the regulation of TRPV4 expression by progesterone, a process that requires a functional PR.
KeywordsEpithelia Vascular smooth muscle Progesterone receptor Promoter Transcription Expression TRPV4 Calcium
We would like to thank Dr. Albert Jordan (CSIC, Barcelona) for the human PRA and PRB expressing vectors. This work was supported by the Spanish Ministry of Science and Innovation (SAF2006-04973), Fondo de Investigación Sanitaria (Red HERACLES RD06/0009), Generalitat de Catalunya (SGR05-266), and Fundació la Marató de TV3 (061331,080430). The authors declare that they have no competing financial interests.
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