NCBI Summary:
The protein encoded by this gene belongs to the family of guanine nucleotide-binding proteins (G proteins), which function as modulators or transducers in various transmembrane signaling systems. G proteins are composed of 3 units: alpha, beta and gamma. This gene encodes one of the alpha subunits (subunit alpha-11). Mutations in this gene have been associated with hypocalciuric hypercalcemia type II (HHC2) and hypocalcemia dominant 2 (HYPOC2). Patients with HHC2 and HYPOC2 exhibit decreased or increased sensitivity, respectively, to changes in extracellular calcium concentrations. [provided by RefSeq, Dec 2013]
General function
Intracellular signaling cascade
Comment
Cellular localization
Cytoplasmic, Plasma membrane
Comment
Ovarian function
Steroid metabolism, Luteinization
Comment
Expression regulated by
LH
Comment
Ovarian superstimulation using FSH combined with equine chorionic gonadotropin (eCG) upregulates mRNA-encoding proteins involved with LH receptor intracellular signaling in granulosa cells from Nelore cows. Castilho AC 2014 et al.
The LH plays a key role in controlling physiological processes in the ovary acting via LH receptor (LHR). In general, the effects of LHR on the regulation of granulosa cell differentiation are mediated mainly via the Gs-protein/adenylyl cyclase/cAMP system; however, the LHR activation could also induce phospholipase C (PLC)/inositol trisphosphate (IP3) via Gq/11 system. Additionally, the expression of G-proteins (GNAS, GNAQ, and GNA11) and PLC has been showed in bovine antral follicle, concomitant with an increase in LHR expression. To gain insight into the effects of superstimulation with FSH (P-36 protocol) or FSH combined with equine chorionic gonadotropin (eCG; P-36/eCG protocol) on the mRNA expression of proteins involved in LHR signaling in bovine granulosa cells, Nelore cows (Bos indicus) were treated with two superstimulatory protocols: P-36 protocol or P-36/eCG protocol (replacement of the FSH by eCG administration on the last day of treatment). Nonsuperstimulated cows were only submitted to estrous synchronization without ovarian superstimulation. The granulosa cells were harvested from follicles and mRNA abundance of GNAS, GNAQ, GNA11, PLCB1, PLCB, PLCB4, and adenylyl cyclase isoforms (ADCY3, ADCY4, ADCY6, ADCY8, and ADCY9) was measured by real-time reserve transcription followed by polymerase chain reaction. No differences on mRNA abundance of target genes were observed in granulosa cells of cows submitted to P-36 protocol compared with control group. However, the cows submitted to P-36/eCG protocol showed upregulation on the mRNA abundance of target genes (except ADCY8) in granulosa cells. Although the P-36 protocol did not regulate mRNA expression of the proteins involved in the signaling mechanisms of the cAMP and IP3 systems, the constant presence of GNAS, GNAQ, GNA11, PLCB1, PLCB3, PLCB4, and adenylyl cyclase isoforms (ADCY3, ADCY4, ADCY6, and ADCY9) mRNA and the upregulation of these genes in granulosa cells from cows submitted to P-36/eCG protocol reinforce the participation of Gq/11/PLC/IP3 signaling as well as Gs-protein/adenylyl cyclase/cAMP system on LHR pathways during bovine granulosa cell differentiation submitted to superstimulatory treatments.
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Ovarian localization
Oocyte, Granulosa, Luteal cells
Comment
Carrasco MP, et al
human granulosa
cells express G proteins of the Gq family (resistant to pertussis toxin) and mRNA
for both G alpha q and G alpha 1 l has been identified by RT-PCR.
Follicle stages
Preovulatory
Comment
Williams CJ, et al reported G protein gene expression during mouse oocyte growth and maturation, and preimplantation embryo development.
Using a reverse transcription-polymerase chain reaction (RT-PCR) assay, the relative levels of mRNAs encoding specific G protein alpha, beta, and gamma subunits were determined in meiotically incompetent oocytes, fully-grown competent oocytes, metaphase II-arrested eggs, one-, two-, and eight-cell embryos, and blastocysts. mRNA transcripts representing all of the heterotrimeric G protein families were present at all of the stages examined, and all underwent significant changes in their patterns of expression. The following heterotrimeric G protein mRNA transcripts were present in oocytes, eggs, or preimplantation embryos: G alpha q family (q, 11, and 14), G alpha 12 family (12 and 13), G alpha i family (i1, i2, i3, t2, z, and s), beta subunits 1, 2, 4, and 5, and gamma subunits 2, 3, 5, and 7. A recently described large molecular weight G protein, G alpha h (Nakaoka et al., 1994: Science 264:1593-1596), was also present, G alpha 15, G alpha t1, G alpha olf, G alpha oA, G beta 3, G gamma 1, and G gamma 8 mRNA transcripts were not detected using this method. The most common pattern of expression observed was a maturation-associated decrease followed by an increase after the two-cell stage. Some transcripts, however, were expressed at low levels until the eight-cell to blastocyst stages, whereas others were expressed at high levels in the oocyte but following maturation declined and remained at a low level throughout preimplantation development.
Phenotypes
Mutations
3 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Ovulation involves the luteinizing hormone-dependent activation of Gq/11 in granulosa cells. Breen SM 2013 et al.
The luteinizing hormone receptor (LHR) activates several families of heterotrimeric G proteins but only the activation of Gs and subsequent generation of cyclic AMP are universally accepted as important mediators of luteinizing hormone (LH) actions. To examine the involvement of the Gq/11 family on the actions of LH we crossed Cyp19Cre and Gaq(f/f);Ga11(-/-) mice to generate mice with a granulosa cell specific deletion of Gaqin the context of a global deletion of Ga11. Granulosa cells from Gaq(f/f);Ga11(-/-);Cre(+) mice have barely detectable levels of Gaq/11, a normal complement of LHR, and respond to LHR activation with a transient increase in cAMP accumulation, but fail to respond with increased inositol phosphate accumulation, an index of the activation of Gaq/11. The LHR-provoked resumption of meiosis, cumulus expansion and luteinization are normal. However, the Gaq(f/f);Ga11(-/-);Cre(+) mice display severe subfertility because many of the oocytes destined for ovulation become entrapped in preovulatory follicles or corpora lutea. Since follicular rupture is known to be dependent on the expression of the progesterone receptor (Pgr) we examined the LHR-induced expression of Pgr and four of its target genes (Adamts-1, Ctsl1, Edn2 and Prkg2). These actions of the LHR were impaired in the ovaries of the Gaq(f/f);Ga11(-/-);Cre(+) mice. We conclude that the defect in follicular rupture is secondary to failure of the LHR to fully induce the expression of the Pgr. This is the first conclusive evidence for the physiological importance of the activation of Gq/11 by the LHR and for the involvement of Gaq/11 in ovulation.
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Species: mouse
Mutation name: type: null mutation fertility: subfertile Comment: Activation of Gq/11 in the Mouse Corpus Luteum is Required for Parturition. Mejia R et al. (2014) Mice with a deletion of Gαq/11 in granulosa cells were previously shown to be subfertile. They also have a reduced ovulatory response due to a deficiency in the ability of the activated luteinizing hormone receptor (LHR) to fully induce the granulosa cell progesterone receptor. Since this conditional deletion of Gαq/11 will interfere with the actions of any G protein coupled receptor that activates Gq/11 in granulosa or luteal cells we sought to determine if the actions of other hormones that contribute to fertility were also impaired. We focused our attention on prostaglandin F2α (PGF2α) because this hormone is known to activate phospholipase C (a prominent Gαq/11 effector) in luteal cells and because the action of PGF2α on luteal cells is the first step in the murine parturition pathway. Our data show that the conditional deletion of Gαq/11 from granulosa cells prevents the ability of PGF2α to induce Akr1c18 in luteal cells. Akr1c18 codes for 20α-hydroxysteroid dehydrogenase, an enzyme that inactivates progesterone. The PGF2α-mediated induction of this enzyme towards the end of pregnancy increases the inactivation of progesterone and precipitates parturition in mice. Thus, the conditional deletion of Gαq/11 from granulosa/luteal cells prevents the progesterone withdrawal that occurs at the end of pregnancy and impairs parturition. This novel molecular defect contributes to the subfertile phenotype of the mice with a deletion of Gαq/11 from granulosa cells.//////////////////
Species: mouse
Mutation name: type: null mutation fertility: subfertile Comment: Gq/11-Dependent Changes in the Murine Ovarian Transcriptome at the End of Gestation. Waite C et al. (2016) 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 post-partum. Ovarian genes up-regulated at the end of gestation in 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) and Enpp2 (which encodes autotaxin, the enzyme responsible for the synthesis of lysophosphatidic acid), genes involved in protein processing and export and reproductive genes such as the Lhcgr; the three genes needed to convert progesterone to estradiol (Cyp17a1, Hsd17b7 and Cyp19a1) and Inha. Activation of ovarian Gq/11 by engaging 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.//////////////////