Endocrine Abstracts (2006) 11 OC10

Progesterone signaling in human myometrium is mediated through two novel membrane G protein coupled receptors

E Karteris1, S Zervou4, Y Pang2, J Dong2, EW Hillhouse3, HS Randeva4 & P Thomas2

1Clinical Sciences Research Institute, Warwick Medical School, Coventry, United Kingdom; 2Marine Science Institute, University of Texas, Austin, Texas, United States; 3Leeds Medical School, Leeds, United Kingdom; 4Biological Sciences, University of Warwick, Coventry, United Kingdom.

One of the hallmarks of parturition in most mammals is a dramatic drop in plasma levels of progesterone (P4), which promotes myometrial relaxation, prior to labor. In humans and some other primates however, the opposite occurs and placental P4 production increases with advancing pregnancy. The expression of nuclear progesterone receptor (PR)-responsive genes is decreased in the primate uterus at term, which suggests ‘functional’ progestin withdrawal involves repression of PR transcriptional activity. Recently, a novel cDNA was discovered in spotted seatrout ovaries that has all the characteristics of a progestin membrane receptor (mPR) and is structurally unrelated to nuclear steroid receptors, but instead has features typical of G-protein coupled receptors (GPCRs). We hypothesises therefore that presence of these receptors in the human myometrium might further influence events leading to ‘functional’ progestin withdrawal. The study was approved by the Local Research Ethics Committee and all patients involved gave their informed consent.

We report the presence of two novel functional membrane progestin receptors (mPRs), mPRα, and mPRβ, 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 steroidal co-activator SRC2. Our data indicate the presence of a novel signalling pathway mediated by mPRs that may result in functional progestin withdrawal, shifting the balance from a quiescent state to one of contraction.

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