Activation of Gq/11 in the Mouse Corpus Luteum Is Required for Parturition

Mejia, Rachel B.; Waite, Courtney; Ascoli, Mario

doi:10.1210/me.2014-1324

Cited by 15 publications

(29 citation statements)

References 57 publications

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“…Likewise, protein expression of NR4A1, the most downstream component of the PGF 2α signaling pathway that directly binds to the Akr1c18 promoter, remained unaffected in KO mice ovaries. Thus, the function of MAMLD1 appears to be independent of the PGF 2α signaling pathway, although mRNA expression of the Gq/11 protein family, a recently identified component of this pathway 11 , was not analyzed in the present study. In contrast, Stat5b and Prlr were markedly upregulated in KO mice ovaries.…”

Section: Discussionmentioning

confidence: 90%

“…Of these, prostaglandin F2α (PGF 2α ) upregulates Akr1c18 via a signaling pathway consisting of PGF 2α , PGF 2α receptor (FP), JUND, and nuclear receptor subfamily 4 group A member 1 (NR4A1, also known as NUR77) 1 9 10 . The Gq/11 protein family also serves as a component of the PGF 2α signaling pathway 11 . Genetic knockout (KO) of Akr1c18 , Fp , or Gα q/11 leads to persistent progesterone production and subsequent parturition failure 5 11 12 13 .…”

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confidence: 99%

“…The Gq/11 protein family also serves as a component of the PGF 2α signaling pathway 11 . Genetic knockout (KO) of Akr1c18 , Fp , or Gα q/11 leads to persistent progesterone production and subsequent parturition failure 5 11 12 13 . In addition, Fp KO perturbs expression of several steroidogenic genes in the corpus luteum, which may also be relevant to delayed parturition 14 .…”

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Parturition failure in mice lacking Mamld1

Miyado

Katsumi

et al. 2015

Sci Rep

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In mice, the onset of parturition is triggered by a rapid decline in circulating progesterone. Progesterone withdrawal occurs as a result of functional luteolysis, which is characterized by an increase in the enzymatic activity of 20α-hydroxysteroid dehydrogenase (20α-HSD) in the corpus luteum and is mediated by the prostaglandin F2α (PGF2α) signaling. Here, we report that the genetic knockout (KO) of Mamld1, which encodes a putative non-DNA-binding regulator of testicular steroidogenesis, caused defective functional luteolysis and subsequent parturition failure and neonatal deaths. Progesterone receptor inhibition induced the onset of parturition in pregnant KO mice, and MAMLD1 regulated the expression of Akr1c18, the gene encoding 20α-HSD, in cultured cells. Ovaries of KO mice at late gestation were morphologically unremarkable; however, Akr1c18 expression was reduced and expression of its suppressor Stat5b was markedly increased. Several other genes including Prlr, Cyp19a1, Oxtr, and Lgals3 were also dysregulated in the KO ovaries, whereas PGF2α signaling genes remained unaffected. These results highlight the role of MAMLD1 in labour initiation. MAMLD1 likely participates in functional luteolysis by regulating Stat5b and other genes, independent of the PGF2α signaling pathway.

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Section: Discussionmentioning

confidence: 90%

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confidence: 99%

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Parturition failure in mice lacking Mamld1

Miyado

Katsumi

et al. 2015

Sci Rep

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“…A role for FP has also been demonstrated in regulating blood pressure where its blockade has been suggested to reduce blood pressure (62). FP is involved in parturition with enhanced PGF2␣ signaling initiating labor by causing smooth muscle contraction of the myometrium (63,64). The AT1R is also expressed in the myometrium with increased levels coinciding with pregnancy (65)(66)(67).…”

Section: Allosteric Interactions In Gpcr Heterodimersmentioning

confidence: 99%

Conformational biosensors reveal allosteric interactions between heterodimeric AT1 angiotensin and prostaglandin F2α receptors

Sleno

Devost

Pétrin

et al. 2017

Journal of Biological Chemistry

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G protein-coupled receptors (GPCRs) are conformationally dynamic proteins transmitting ligand-encoded signals in multiple ways. This transmission is highly complex and achieved through induction of distinct GPCR conformations, which preferentially drive specific receptor-mediated signaling events. This conformational capacity can be further enlarged via allosteric effects between dimers, warranting further study of these effects. Using GPCR conformation-sensitive biosensors, we investigated allosterically induced conformational changes in the recently reported F prostanoid (FP)/angiotensin II type 1 receptor (AT1R) heterodimer. Ligand occupancy of the AT1R induced distinct conformational changes in FP compared with those driven by PGF2α in bioluminescence resonance energy transfer (BRET)-based FP biosensors engineered with luciferase (RLuc) as an energy donor in the C-tail and fluorescein arsenical hairpin binder (FlAsH)-labeled acceptors at different positions in the intracellular loops. We also found that this allosteric communication is mediated through Gα and may also involve proximal (phospholipase C) but not distal (protein kinase C) signaling partners. Interestingly, β-arrestin-biased AT1R agonists could also transmit a Gα-dependent signal to FP without activation of downstream Gα signaling. This transmission of information was specific to the AT1R/FP complex, as activation of Gα by the oxytocin receptor did not recapitulate the same phenomenon. Finally, information flow was asymmetric in the sense that FP activation had negligible effects on AT1R-based conformational biosensors. The identification of partner-induced GPCR conformations may help identify novel allosteric effects when investigating multiprotein receptor signaling complexes.

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“…Studies with mice harboring a granulosa/luteal cell-specific deletion of G α q/11 have demonstrated that the differentiation of granulosa cells into luteal cells, as well as the establishment and maintenance of pregnancy, does not require G q/11 [ 3 , 4 ]. Parturition, on the other hand, is dependent on the prostaglandin F2α (PGF2α)-provoked activation of luteal G q/11 [ 4 ]. A conditional deletion of G α q/11 from granulosa/luteal cells disrupts the actions of PGF2α on luteal cells that normally occur toward the end of gestation [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Gq/11-Dependent Changes in the Murine Ovarian Transcriptome at the End of Gestation1

Waite

Mejia

Ascoli

2016

Biology of Reproduction

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Parturition in rodents is highly dependent on the engagement of the luteal prostaglandin F2 alpha receptor, which, through activation of the Gq/11 family of G proteins, increases the expression of Akr1c18, leading to an increase in progesterone catabolism. To further understand the involvement of Gq/11 on luteolysis and parturition, we used microarray analysis to compare the ovarian transcriptome of mice with a granulosa/luteal cell-specific deletion of Galphaq/11 with their control littermates on Day 18 of pregnancy, when mice from both genotypes are pregnant, and on Day 22, when mice with a granulosa/luteal cell-specific deletion of Galphaq/11 are still pregnant but their control littermates are 1–2 days postpartum. Ovarian genes up-regulated at the end of gestation in a Galphaq/11 -dependent fashion include genes involved in focal adhesion and extracellular matrix interactions. Genes down-regulated at the end of gestation in a Galphaq/11-dependent manner include Serpina6 (which encodes corticosteroid-binding globulin); Enpp2 (which encodes autotaxin, the enzyme responsible for the synthesis of lysophosphatidic acid); genes involved in protein processing and export; reproductive genes, such as Lhcgr; the three genes needed to convert progesterone to estradiol (Cyp17a1, Hsd17b7, and Cyp19a1); and Inha. Activation of ovarian Gq/11 by engagement of the prostaglandin F2 alpha receptor on Day 18 of pregnancy recapitulated the regulation of many but not all of these genes. Thus, although the ovarian transcriptome at the end of gestation is highly dependent on the activation of Gq/11, not all of these changes are dependent on the actions of prostaglandin F2 alpha.

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Activation of Gq/11 in the Mouse Corpus Luteum Is Required for Parturition

Cited by 15 publications

References 57 publications

Parturition failure in mice lacking Mamld1

Parturition failure in mice lacking Mamld1

Conformational biosensors reveal allosteric interactions between heterodimeric AT1 angiotensin and prostaglandin F2α receptors

Gq/11-Dependent Changes in the Murine Ovarian Transcriptome at the End of Gestation1

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