Kimura et al. (1992) reported the structure
and expression of the human oxytocin receptor cDNA isolated by expression cloning. The encoded receptor was a
388-amino acid polypeptide with 7 transmembrane domains typical of G protein-coupled receptors. The oxytocin
receptor, expressed in Xenopus oocytes, specifically responded to oxytocin and induced an inward membrane current.
Messenger RNAs for the receptor were of 2 sizes, 3.6 kb in breast and 4.4 kb in ovary, endometrium, and myometrium.
NCBI Summary:
The protein encoded by this gene belongs to the G-protein coupled receptor family and acts as a receptor for oxytocin. Its activity is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. The oxytocin-oxytocin receptor system plays an important role in the uterus during parturition.
Oxytocin receptors in the primate ovary: molecular identity and link to apoptosis in human granulosa cells. Saller S et al. BACKGROUND Oxytocin (OT) is produced by granulosa cells (GCs) of pre-ovulatory ovarian follicles and the corpus luteum (CL) in some mammalian species. Actions of OT in the ovary have been linked to luteinization, steroidogenesis and luteolysis. Human IVF-derived (h)GCs possess a functional OT receptor (OTR), linked to elevation of intracellular Ca(2+), but molecular identity of the receptor for OT in human granulosa cells (hGCs) and down-stream consequences are not known. METHODS AND RESULTS RT-PCR, sequencing and immunocytochemistry identified the genuine OTR in hGCs. OT (10 nM-10 microM) induced elevations of intracellular Ca(2+) levels (Fluo-4 measurements), which were blocked by tocinoic acid (TA; 50 microM, a selective OTR-antagonist). Down-stream effects of OTR-activation include a concentration dependent decrease in cell viability/metabolism, manifested by reduced ATP-levels, increased caspase3/7-activity (P < 0.05) and electron microscopical signs of cellular regression. TA blocked all of these changes. Immunoreactive OTR was found in the CL and GCs of large and, surprisingly, also small pre-antral follicles of the human ovary. Immunoreactive OTR in the rhesus monkey ovary was detected in primordial and growing primary follicles in the infantile ovary and in follicles at all stages of development in the adult ovary, as well as the CL: these results were corroborated by RT-PCR analysis of GCs excised by laser capture microdissection. CONCLUSIONS Our study identifies genuine OTRs in human and rhesus monkey GCs. Activation by high levels of OT leads to cellular regression in hGCs. As GCs of small follicles also express OTRs, OT may have as yet unkown functions in follicular development.
Wuttke W, et al. reviewed luteotropic and luteolytic effects of oxytocin in the porcine corpus luteum.
Wathes DC, et al. reviewed the control of synthesis and secretion of ovarian oxytocin in ruminants.
Fuchs AR reviewed that
(1) Oxytocin is synthesized in the luteal cells of all species so far studied, including the human.
Vasopressin is also synthesized, but at a much lower rate. (2) The oxytocin-neurophysin gene is
expressed in granulosa cells and granulosa-derived luteal cells but not in theca cells. Ovulation or
spontaneous luteinization initiates the gene expression which peaks in the early luteal phase and ceases around mid-cycle. (3) Luteal oxytocin concentrations rise with considerable delay after the peak of
specific mRNA and reach maximal levels around mid-cycle. Oxytocin concentrations fall to low levels
in the late luteal phase and in pregnancy. (4) Thecal tissue produces substances such as catecholamines
and ascorbic acid that stimulate oxytocin secretion in granulosa cells. The adrenergic innervation of
thecal tissue provides a source of catecholamines and may therefore serve a modulatory function in
ovarian oxytocin secretion. (5) Oxytocin has little or no direct effect on luteal progesterone production.
(6) Oxytocin inhibits LH-stimulated prostacyclin production in luteal cells of cows. Oxytocin may induce
the release of PGF-2 alpha or lipo-oxygenase products from the ovary but this has not yet been
documented. (7) PGF-2 alpha releases oxytocin from the ovary but does not turn off its synthesis. (8) The
concept that ovarian oxytocin participates in the luteolytic process is gaining acceptance. In some species
(sheep, goat) ovarian oxytocin acts as a hormone causing PGF-2 alpha release from the uterus. In others
it acts in a paracrine or autocrine fashion on ovarian prostanoid production (cow, possibly primates).
Expression regulated by
FSH, Steroids
Comment
Uenoyama Y, et al. reported the regulation of oxytocin receptors in bovine granulosa cells. Both FSH and estradiol are
regulators of OT receptors in granulosa cells during follicular development. FSH might down-regulate
OT receptors in this phase, and the inhibitory effects of FSH are mediated by the adenylate
cyclase-cAMP-protein kinase A system. Furthermore, estradiol seems to play a role in neutralizing the
effects of FSH.
Ovarian localization
Cumulus, Granulosa, Luteal cells
Comment
Einspanier A et al reported that local oxytocin (OT) system is part of the luteinization process in the
preovulatory follicle of the marmoset monkey.
Before the
endogenous LH increase, OT immunoreactivity was detectable at low levels in most antral follicles,
where its presence was confined to antral granulosa cell (GC) layers. In contrast, immunoreactivity for
the OT receptor (OTR) was localized primarily in the basal GC layer. After application of exogenous
hCG, there was a marked enhancement in both the staining intensity and the number of cells positive for
OT and the OTR in all GC layers of antral follicles, especially in the preovulatory follicle. Secretion of authentic OT was demonstrated from
cultured GC obtained before the LH surge, with highest amounts in cells cultured from preovulatory as
opposed to smaller antral follicles. OT production could be stimulated by the application of hCG to the
GC cultured from preovulatory follicles, whereas the gonadotropin was without effect on GC from small
follicles. FSH had no effect on OT production by GC from either follicle type. Application of OT to the
cultures caused an increase in progesterone production by GC from large preovulatory follicles but was
without effect on steroidogenesis by cells from small antral follicles. These results describing the
presence and distribution of OT and OTR and their modulation by hCG, as well as the luteotrophic effect
of OT in cultured GC from preovulatory follicles, implicate OT as a paracrine mediator in the
luteinization process in the primate ovary.
Okuda K, et al. reported functional oxytocin receptors in bovine granulosa cells.
Furuya K et al reported the expression of
oxytocin and oxytocin receptor in cumulus/luteal cells and the
effect of oxytocin on embryogenesis in fertilized oocytes.
Cumulus cells
with mature oocytes were obtained from experimental and clinical in vitro fertilization-embryo transfer
(IVF-ET) programs. OT and OTR gene expression was analyzed with reverse transcriptase-polymerase
chain reaction (RT-PCR) and RT-PCR/single strand conformation polymorphism (SSCP). OT gene
expression was detected in mouse and human cumulus cells. Furthermore, OTR
gene expression was demonstrated in human cumulus cells, and a weak positive signal was
observed in human oocytes. Immunocytochemical staining of OTR was detected in human
cumulus cells. The rate of mouse blastocyst development was significantly higher in the group cultured
with OT than that without OT.