The activity of hormone-sensitive adenylate cyclase is regulated by at least 2 guanine nucleotide-binding proteins (G proteins), 1 stimulatory (Gs) and 1 inhibitory (Gi). Each is a heterotrimer; each has a unique alpha chain, but the beta and gamma chains are apparently identical polypeptides of 35,000 and 8,000 daltons, respectively. The GTP-binding protein Gs couples hormone-receptor binding to adenylyl cylase activation. The alpha subunit of the Gs protein exists in 2 predominant species of molecular weights 52,000 and 45,000, which are thought to be products of a single gene.
Heterotrimeric guanine nucleotide-binding proteins transduce extracellular signals received by transmembrane receptors to effector proteins. Each subunit of the G protein complex is encoded by a member of 1 of 3 corresponding gene families. There are16 different members of the alpha-subunit family, 5 different members of the beta-subunit family, and 11 different members of the gamma-subunit family, as described in mammals.
NCBI Summary:
This locus has a highly complex imprinted expression pattern. It gives rise to maternally, paternally, and biallelically expressed transcripts that are derived from four alternative promoters and 5' exons. Some transcripts contain a differentially methylated region (DMR) at their 5' exons, and this DMR is commonly found in imprinted genes and correlates with transcript expression. An antisense transcript is produced from an overlapping locus on the opposite strand. One of the transcripts produced from this locus, and the antisense transcript, are paternally expressed noncoding RNAs, and may regulate imprinting in this region. In addition, one of the transcripts contains a second overlapping ORF, which encodes a structurally unrelated protein - Alex. Alternative splicing of downstream exons is also observed, which results in different forms of the stimulatory G-protein alpha subunit, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular reponses. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene result in pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type 1b, Albright hereditary osteodystrophy, pseudopseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors. [provided by RefSeq, Aug 2012]
General function
Comment
Mantovani G, et al reported the predominant maternal origin of transcription of Gs alpha
in human thyroid gland and gonads.
Mutations in the guanine nucleotide binding a-subunit 1 gene (GNAS1) cause
Albright's hereditary osteodistrophy, and the parent of transmission
determines variable phenotypic expression of the disease. This has suggested
that GNAS1 maybe under tissue-specific imprinting control, although studies so
far available have failed to clearly define the pattern of GNAS1 expression in
humans. To establish if GNAS1 is imprinted in human endocrine tissues, the authors
selected 14 thyroid, 10 granulosa cell, 13 pituitary (3 normal glands, 7
GH-secreting adenomas, and 3 nonfunctioning adenomas), 3 adrenal, and 11
lymphocyte samples shown to be heterozygous for a known polymorphism in exon
5. RNA from these tissues was analyzed by RT-PCR, and expression from both
parental alleles was evaluated by enzymatic digestion and subsequent
quantification of the resulting fragments. The parental origin of Gsalpha was
assessed by evaluating neuroendocrine secretory protein 55 and extra large
as-like protein transcripts, which have been shown to be monoallelically and
parent-specifically expressed from the maternal and paternal allele,
respectively. By this approach, the great majority of thyroid (n = 12),
ovarian (n = 7), and pituitary (n = 11) samples showed an almost exclusive or
significantly predominant expression of the maternal allele over the paternal
one, whereas in lymphocyte and adrenal samples both alleles were equally
expressed.The results provide evidence for a predominant maternal origin of
GNAS1 transcripts in different human adult endocrine tissues, particularly
thyroid, ovary, and pituitary, and strongly suggest that this mechanism may
play a crucial role in the determination of the phenotypic expression of
Albright's hereditary osteodistrophy.
The methylation status in GNAS clusters May Be an epigenetic marker for oocyte quality. Li QN et al. (2020) During follicle growth, DNA methylation is gradually established, which is important for oocyte developmental competence. Due to the facts that oocytes from prepubertal individuals show reduced developmental outcomes when compared to those from sexually mature individuals, and the fact that oocytes derived from in vitro follicle culture have much lower developmental competence, it is worth exploring whether prepubertal superovulation and in vitro follicle culture will cause changes in DNA methylation imprinting status in oocytes. In this study, we found that the CpG island in maternally imprinted GNAS clusters was hypermethylated in the MII-stage oocytes from sexually mature mice, but was hypomethylated in oocytes from prepuberty individuals. The GNAS clusters in the MII-stage oocytes obtained by in vitro follicle culture showed heterogeneous methylation levels, indicating different qualities of oocytes, however, three other maternally imprinted genes, Peg1, Lot1 and Impact, were all hypermethylated in the MII-stage oocytes derived from both prepubertal superovulation and in vitro follicle culture. Taken together, the findings suggest that the methylation status in GNAS clusters may potentially represent a novel epigenetic marker for oocyte quality detection.//////////////////
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, Cumulus, Granulosa, Theca, Luteal cells, Small luteal cells, Large luteal cells
Comment
Mehlmann LM, et al reported that Meiotic arrest in the mouse follicle is maintained by a Gs protein in the oocyte.
The mammalian ovarian follicle consists of a multilayered complex of somatic cells that surround the oocyte. A signal from the follicle cells keeps the oocyte cell cycle arrested at prophase of meiosis I until luteinizing hormone from the pituitary acts on the follicle cells to release the arrest, causing meiosis to continue. Here the authors show that meiotic arrest can be released in mice by microinjecting the oocyte within the follicle with an antibody that inhibits the stimulatory heterotrimeric GTP-binding protein Gs. This indicates that Gs activity in the oocyte is required to maintain meiotic arrest within the ovarian follicle and suggests that the follicle may keep the cell cycle arrested by activating Gs.
Follicle stages
Primordial, Primary, Secondary, Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
Mutations
1 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Mutations in the GNAS1 gene are associated with pseudohypoparathyroidism, type IA (OMIM 103580) and McCune-Albright syndrome (OMIM MAS; 174800). The change in the gene is an inactivating mutation or an activating mutation, respectively. The activating mutation in the McCune-Albright syndrome is usually present in the mosaic state; the nonmosaic state for most activating mutations is presumably lethal to the embryo. The leading endocrinologic feature is precocious puberty, which occurs in over half of female cases. Menstruation may occur in the first months of life. Excessive secretion of growth hormone with gigantism, hyperadrenocorticism with Cushing syndrome, and gynecomastia have been observed. In specific instances, it has been demonstrated that the Cushing syndrome is due to multinodular change in the adrenals and the hyperthyroidism to multinodular toxic goiter.
Laven et al. (2001) et al presented the first longitudinal assessment of ovarian dysfunction in an adult patient with McCune-Albright syndrome. Their report provided evidence for persistent autonomous unilateral ovarian dysfunction during early adulthood in McCune-Albright syndrome not compatible with normal fertility.