Research ArticleHormone Signaling

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

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Sci. Signal.  14 Aug 2018:
Vol. 11, Issue 543, eaam6558
DOI: 10.1126/scisignal.aam6558

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How progesterone stimulates cilia

The transport of eggs along the ciliated epithelium of the oviduct depends on the ciliary beat frequency (CBF), a process that requires intracellular Ca2+ signaling. The hormone progesterone is thought to accelerate egg transport along the oviduct. Because any rapid effects of progesterone on CBF would be incompatible with its function as a transcriptional regulator, Jung et al. investigated how progesterone affected Ca2+ signaling in mouse ciliated oviduct cells. They found that progesterone stimulated increased intracellular Ca2+ concentrations in a process that required the nonselective cationic channel TRPV4 and the stepwise activation of GABAA and GABAB receptors, which physically associated with each other in response to progesterone and GABAergic agonists. Together, these data implicate progesterone and GABA receptor agonists in the rapid acceleration of cilial activity in the oviduct.

Abstract

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 (GABAA/B) in the mouse oviduct that was characterized by oscillatory Ca2+ 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 GABAA (α1 to α3, β2, and β3), and GABAB1 in P4-induced responses. TRPV4-mediated Ca2+ entry in close proximity to the inositol trisphosphate receptor was required to initiate and maintain Ca2+ oscillations after P4 binding to GABAA and transactivation of Gi/o protein–coupled GABAB receptors. Coimmunoprecipitation experiments and imaging of native tissue and HEK 293T cells demonstrated the close association of GABAA and GABAB1 receptors and the activation of Gi/o proteins in response to P4 and GABA receptor agonists, confirming a molecular mechanism in which P4 and GABAergic agonists cooperatively stimulate cilial beating.

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