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Progesterone Signaling in Human Myometrium through Two Novel Membrane G Protein-Coupled Receptors: Potential Role in Functional Progesterone Withdrawal at Term

Division of Clinical Science (E.K.), Warwick Medical School and Biomedical Research Institute (S.Z., H.S.R.), Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom; Marine Science Institute (Y.P., J.D., P.T.), University of Texas at Austin, Port Aransas, Texas 78373; and The Office of the Dean (E.W.H.), The Medical School, University of Leeds, Leeds LS2 9NL, United Kingdom

Address all correspondence and requests for reprints to: Professor Peter Thomas, The University of Texas at Austin, Marine Science Institute, 750 Channel View Drive, Port Aransas, Texas 78373. E-mail: thomas{at}utmsi.utexas.edu.

Progestin withdrawal is a crucial event for the onset of labor in many mammalian species. However, in humans the mechanism of a functional progestin withdrawal is unclear, because progestin concentrations do not drop in maternal plasma preceding labor. We report the presence of two novel functional membrane progestin receptors (mPRs), mPR and mPRß, in human myometrium that are differentially modulated during labor and by steroids in vitro. The mPRs are coupled to inhibitory G proteins, resulting in a decline in cAMP levels and increased phosphorylation of myosin light chain, both of which facilitate myometrial contraction. Activation of mPRs leads to transactivation of PR-B, the first evidence for cross-talk between membrane and nuclear PRs. Progesterone activation of the mPRs leads also to a decrease of the steroid receptor coactivator 2. Our data indicate the presence of a novel signaling pathway mediated by mPRs that may result in a functional progestin withdrawal, shifting the balance from a quiescent state to one of contraction.

NURSA Molecule Pages Link:

Coregulators:   CBP  |  SRC-1  |  GRIP1  |  AIB1

Ligands:   Dexamethasone  |  17β-Estradiol  |  Progesterone

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