Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term.
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), mPRalpha and mPRbeta, 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.
Division of Clinical Science, University of Warwick, Coventry, UK.
Emmanouil
E
Karteris
Sevasti
S
Zervou
Yefei
Y
Pang
Jing
J
Dong
Edward W
EW
Hillhouse
Harpal S
HS
Randeva
Peter
P
Thomas
D000123:Acetyltransferases / Q000378:metabolism; D018929:Cell Culture Techniques; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D006801:Humans; D007743:Labor, Obstetric / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D009215:Myometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3; D010766:Phosphorylation; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism* / Q000502:physiology; D011980:Receptors, Progesterone / Q000378:metabolism* / Q000502:physiology; D047929:Term Birth / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
D000123:Acetyltransferases; D004967:Estrogens; D019204:GTP-Binding Proteins; D051548:Histone Acetyltransferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018994:Myosin Light Chains; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D056921:Nuclear Receptor Coactivator 3; D011374:Progesterone; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D011980:Receptors, Progesterone; D015534:Trans-Activators; D014157:Transcription Factors; C513556:PAQR7 protein, human; C513557:PAQR8 protein, human; C538859:NCOA1 protein, human; C538866:NCOA3 protein, human