Functional coupling of GABAA/B receptors and the channel TRPV4 mediates rapid progesterone signaling in the oviduct

The molecular mechanism by which progesterone (P4) modulates the transport of ova and embryos along the oviduct is not fully resolved. We report a rapid response to P4 and agonists of γ-aminobutyric acid receptors A and B (GABA A/B ) in the mouse oviduct that was characterized by oscillatory Ca 2+ signals and increased ciliary beat frequency (CBF). Pharmacological manipulation, genetic ablation, and siRNA-mediated knockdown in oviductal cells, as well as overexpression experiments in HEK 293T cells, confirmed the participation of the cationic channel TRPV4, different subunits of GABA A (α1 to α3, β2, and β3), and GABA B1 in P4-induced responses. TRPV4-mediated Ca 2+ entry in close proximity to the inositol trisphosphate receptor was required to initiate and maintain Ca 2+ oscillations after P4 binding to GABA A and transactivation of G i/o protein–coupled GABA B receptors. Coimmunoprecipitation experiments and imaging of native tissue and HEK 293T cells demonstrated the close association of GABA A and GABA B1 receptors and the activation of G i/o proteins in response to P4 and GABA receptor agonists, confirming a molecular mechanism in which P4 and GABAergic agonists cooperatively stimulate cilial beating.