Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mature antral follicles were removed from the ovaries of pregnant mare serum gonadotropin (PMSG)-primed hamsters at proestrus prior to the LH surge. Following various incubation times with either LH (ovine) or FSH (rat), cAMP levels were determined in whole follicles, cumulus-oocyte complexes (COCs), and zona-intact or zona-free oocytes. LH produced a dose- and time-dependent change in follicle cAMP but had a minimal effect on the COCs and caused no change in cAMP in zona-free oocytes. By contrast, rFSH stimulated a small rise in follicular cAMP but significantly increased levels in COCs and zona-free oocytes. In a second series of experiments follicles were exposed for short periods to various additives after which they were washed and returned to hormone-free medium for a 6-hr total incubation period. LH (1 microgram/ml) initiated maturation in follicle-enclosed oocytes after a 5- to 15-min exposure period while groups incubated with 100 ng/ml required 60 min. FSH did not stimulate maturation after a 60-min exposure and when combined with 1 microgram or 100 ng/ml of LH negated the maturational effects seen with LH alone. It was postulated that the reason that lower concentrations of LH did not stimulate maturation following short-term incubations was due to an insufficient rise in cAMP. However, neither dbcAMP nor forskolin augmented the capacity of LH to initiate maturation following short-term exposure. By contrast dbcGMP and the guanylate cyclase activator, sodium nitroprusside (NP) did augment the maturation-inducing effects of LH. NP + LH raised cGMP concentrations in the follicle and oocyte and decreased follicular cAMP at 30 and 120 min. The results of this study indicate that the component cells within a follicle respond selectively with cAMP changes, depending on the gonadotropin, in a variable time- and dose-dependent manner. While LH is the more potent activator of cAMP in whole follicles, cAMP levels in the cumulus oophorus and oocyte show the greatest increase following exposure to FSH. LH was the more potent initiator of maturation, possibly through its effects on the mural granulosa cells. FSH appears to exert a more inhibitory role which may be due in part to elevated cAMP levels and/or a putitative inhibitor in the COC and oocyte.
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PMID:Cyclic AMP changes in the component cells of Graafian follicles: possible influences on maturation in the follicle-enclosed oocytes of hamsters. 302 32

In the testis the mesenchymally derived peritubular cells produce a paracrine factor, PModS, that mediates mesenchymal-epithelial interactions and modulates Sertoli cell functions essential for the process of spermatogenesis. PModS has a more dramatic effect on Sertoli cell differentiated functions in vitro than any regulatory agent previously shown to influence the cells, including FSH. The current study initiates an investigation of the pharmacology of PModS through an analysis of several common signal transduction pathways. PModS was found to stimulate cGMP levels in Sertoli cells and maintain elevated levels for up to 5 days in culture. PModS had no influence on cAMP levels. In contrast, FSH stimulated cAMP, but had no influence on cGMP levels. For comparison, an agent known to influence cGMP levels, atrial naturetic factor (ANF), was used to treat Sertoli cells. ANF caused a dramatic increase in Sertoli cell cGMP levels within minutes of treatment, but did not maintain elevated cGMP levels after a 72-h treatment. Although ANF increased guanylate cyclase in whole Sertoli cell homogenates and particulate fractions, PModS did not directly influence guanylate cyclase activity. As previously shown, PModS stimulates transferrin expression as a marker of Sertoli cell differentiated function. Agents that elevate cellular cGMP, including ANF, sodium nitroprusside, and 8-bromo-cGMP, did not influence Sertoli cell transferrin expression. In addition, these agents did not influence the actions of PModS or FSH. Therefore, cGMP does not appear to directly mediate the actions of PModS. As an alternative signal transduction pathway, calcium mobilization and inositol phosphate (IP) metabolism were examined. PModS did not alter calcium uptake or intracellular calcium mobilization. PModS also did not influence the levels of inositol mono-, bis-, or trisphosphates, whereas calf serum did stimulate levels of all three IP metabolites in Sertoli cells. Therefore, PModS does not appear to act through a mobilization of calcium or increased metabolism of IP. A final signal transduction pathway involving phosphorylation was also examined. PModS treatment was found to increase tyrosine phosphorylation of specific proteins in a crude Sertoli cell cytosol preparation. Genistein is an inhibitor of tyrosine kinases and was found to reduce PModS actions at a 3.7-microM concentration of genistein and inhibit PModS actions at a 37-microM concentration of genistein. Therefore, PModS may act through a tyrosine phosphorylation event that remains to be elucidated. Combined observations indicate that PModS does not use cyclic nucleotides, calcium mobilization, or IP metabolism as a signal transduction pathway.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of Sertoli cell differentiation by the testicular paracrine factor PModS: analysis of common signal transduction pathways. 790 30

Neurons containing neural nitric oxide synthase (nNOS) are found in various locations in the hypothalamus and, in particular, in the paraventricular and supraoptic nuclei with axons which project to the median eminence and extend into the neural lobe where the highest concentrations of NOS are found in the rat. Furthermore, nNOS is also located in folliculostellate cells and LH gonadotropes in the anterior pituitary gland. To define the role of NO in the release of hypothalamic peptides and pituitary hormones, we injected an inhibitor of NOS, Ng-monomethyl-L-arginine (NMMA) or a releasor of NO, nitroprusside (NP) into the third ventricle (3V) of conscious castrate rats and determined the effect on the release of various pituitary hormones. In vitro, we incubated medial basal hypothalamic (MBH) fragments and studied inhibitors of NO synthase and also releasors of NO. The results indicate that NOergic neurons play an important role in stimulating the release of corticotrophin-releasing hormone (CRH), luteinizing hormone releasing-hormone (LHRH), prolactin-RH's, particularly oxytocin, growth hormone-RH (GHRH) and somatostatin, but not FSH-releasing factor from the hypothalamus. NO stimulates the release of LHRH, which induces sexual behavior, and causes release of LH from the pituitary gland. The intrahypothalamic pathway by which NO controls LHRH release is as follows: glutamergic neurons synapse with noradrenergic terminals in the MBH which release nonepinephrine (NE) that acts on alpha 1 receptors on the NOergic neuron to increase intracellular free Ca++ which combines with calmodulin to activate NOS. The NOS diffuses to the LHRH terminal and activates guanylate cyclase (GC), cyclooxygenase and lipoxygenase causing release of LHRH via release of cyclic GMP, PGE2 and leukotrienes, respectively. Alcohol and cytokines can block LHRH release by blocking the activation of cyclooxygenase and lipoxygenase without interfering with the activation of GC. GABA also blocks the response of the LHRH neurons to NO and recent experiments indicate that granulocyte macrophage colony-stimulating factor (GMCSF) blocks the response of the LHRH neuron to NP by activation of GABA neurons since the blockade can be reversed by the competitive inhibitor of GABAa receptors, bicuculine.
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PMID:The role of nitric oxide (NO) in control of hypothalamic-pituitary function. 939 93

Gonadotropin secretion by the pituitary gland is under the control of luteinizing hormone-releasing hormone (LHRH) and the putative follicle-stimulating hormone-releasing factor (FSHRF). Lamprey III LHRH is a potent FSHRF in the rat and appears to be resident in the FSH controlling area of the rat hypothalamus. It is an analog of mammalian LHRH and may be the long-sought FSHRF. Gonadal steroids feedback at hypothalamic and pituitary levels to either inhibit or stimulate the release of LH and FSH, which is also affected by inhibin and activin secreted by the gonads. Important control is exercised by acetylcholine, norepinephrine (NE), dopamine, serotonin, melatonin and glutamic acid (GA). Furthermore, LH and FSH also act at the hypothalamic level to alter secretion of gonadotropins. More recently, growth factors have been shown to have an important role. Many peptides act to inhibit or increase release of LH, and the sign of their action is often reversed by estrogen. A number of cytokines act at the hypothalamic level to suppress acutely the release of LH but not FSH. NE, GA and oxytocin stimulate LHRH release by activation of neural nitric oxide synthase (nNOS). The pathway is as follows: oxytocin and/or GA activate NE neurons in the medial basal hypothalamus (MBH) that activate NOergic neurons by alpha1 receptors. The NO released diffuses into LHRH terminals and induces LHRH release by activation of guanylate cyclase (GC) and cyclooxygenase. NO not only controls release of LHRH bound for the pituitary, but also that which induces mating by actions in the brain stem. An exciting recent development has been the discovery of the adipocyte hormone, leptin, a cytokine related to tumor necrosis factor-alpha (TNF-alpha). In the male rat, leptin exhibits a high potency to stimulate FSH and LH release from hemipituitaries incubated in vitro, and increases the release of LHRH from MBH explants by stimulating the release of NO. LHRH and leptin release LH by activation of NOS in the gonadotropes. The NO released activates GC that releases cyclic GMP which induces LH release. Leptin induces LH release in conscious, ovariectomized estrogen-primed female rats, presumably by stimulating LHRH release. At the effective dose of estrogen to activate LH release, FSH release is inhibited. Leptin may play an important role in induction of puberty and control of LHRH release in the adult as well.
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PMID:Hypothalamic control of FSH and LH by FSH-RF, LHRH, cytokines, leptin and nitric oxide. 973 Jun 86

Gonadotropin secretion by the pituitary gland is under the control of luteinizing hormone-releasing hormone (LHRH) and the putative follicle stimulating hormone-releasing factor (FSHRF). Lamprey III LHRH is a potent FSHRF in the rat and seems to be resident in the FSH controlling area of the rat hypothalamus. It is an analog of mammalian LHRH and may be the long sought FSHRF. Gonadal steroids feedback at hypothalamic and pituitary levels to either inhibit or stimulate the release of LH and FSH, which is also affected by inhibin and activin secreted by the gonads. Important control is exercised by acetylcholine, norepinephrine (NE), dopamine, serotonin, melatonin, and glutamic acid (GA). Furthermore, LH and FSH also act at the hypothalamic level to alter secretion of gonadotropins. More recently, growth factors have been shown to have an important role. Many peptides act to inhibit or increase release of LH and the sign of their action is often reversed by estrogen. A number of cytokines act at the hypothalamic level to suppress acutely the release of LH but not FSH. NE, GA, and oxytocin stimulate LHRH release by activation of neural nitric oxide synthase (nNOS). The pathway is as follows: oxytocin and/or GA activate NE neurons in the medial basal hypothalamus (MBH) that activate NOergic neurons by alpha, (alpha 1) receptors. The NO released diffuses into LHRH terminals and induces LHRH release by activation of guanylate cyclase (GC) and cyclooxygenase. NO not only controls release of LHRH bound for the pituitary, but also that which induces mating by actions in the brain stem. An exciting recent development has been the discovery of the adipocyte hormone, leptin, a cytokine related to tumor necrosis factor (TNF) alpha. In the male rat, leptin exhibits a high potency to stimulate FSH and LH release from hemipituitaries incubated in vitro, and increases the release of LHRH from MBH explants. LHRH and leptin release LH by activation of NOS in the gonadotropes. The NO released activates GC that releases cyclic GMP, which induces LH release. Leptin induces LH release in conscious, ovariectomized estrogen-primed female rats, presumably by stimulating LHRH release. At the effective dose of estrogen to activate LH release, FSH release is inhibited. Leptin may play an important role in induction of puberty and control of LHRH release in the adult as well.
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PMID:Hypothalamic control of gonadotropin secretion by LHRH, FSHRF, NO, cytokines, and leptin. 978 37

Natriuretic peptides form a family of structurally related peptides known to regulate salt and water homeostasis and to cause vasodilation. Synthesis of atrial (ANP), brain (BNP), and C-type (CNP) natriuretic peptides occurs mainly in the heart and brain and has been identified recently in the female reproductive tract. The expression of ANP and CNP as well as their cognate guanylyl cyclase receptors (NPR-A and NPR-B, respectively) have been detected in the rat ovary. We have shown previously that the expression of the natriuretic peptides and their receptors in the rat ovary appears to be modulated by the estrous cycle. In the present study we have evaluated the expression of the natriuretic peptide system (peptide and receptor) in ovarian cells (granulosa and thecal-interstitial cells) obtained from immature female rats treated with either diethylstilbestrol (DES), an estrogen analog, or equine CG (eCG), a gonadotropin that possesses both LH and FSH activity. Using a whole cell RRA, we found that CNP binding was increased by 2-fold in granulosa cells taken from animals treated with either DES or eCG. Semiquantitative RT-PCR revealed that granulosa cells from DES- or eCG-treated animals have increased levels of NPR-B messenger RNA (mRNA) transcripts, which was in good agreement with the increased binding. The activity of the receptors was assessed by ligand-dependent stimulation of cGMP release. CNP, but not ANP, stimulated the release of cGMP from granulosa cells obtained from DES-treated, but not from eCG-treated, animals. The relative levels of CNP mRNA in granulosa cells were unaltered by either DES or eCG treatment. In contrast, CNP mRNA levels were increased more than 2-fold, but only in theca-interstitial from the eCG-treated animals. Our results indicate that CNP and NPR-B are expressed in the ovary, and their expression is responsive to hormonal treatments. Furthermore, expression of these components of the natriuretic peptide system appears to be compartmentalized, with CNP being derived from the extrafollicular compartment and acting, through NPR-B, on the granulosa cells.
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PMID:B-type natriuretic peptide receptor expression and activity are hormonally regulated in rat ovarian cells. 1065 Sep 35

The production of a viable oocyte is dependent upon the critical influences of gonadotrophins on follicular development, granulosa cell maturation, ovulation, and luteinization. While the effects of LH and FSH are due in large part to cyclic AMP-dependent signalling mechanisms, it is clear that a number of other factors modulate the actions of gonadotrophins on the ovary via activation of alternative signalling pathways. In this regard, recent studies indicate that the second messenger guanosine 3',5'-cyclic monophosphate (cGMP) mediates a wide range of influences on the ovary. Nitric oxide (NO) is a major regulator of cGMP production via its action on soluble guanylyl cyclase, while natriuretic peptides activate receptors with intrinsic guanylyl cyclase activities. In addition, other factors known to influence ovarian functions are now recognized to act via NO/cGMP pathways. This report will review these previous findings and present new data demonstrating the inhibitory influence of cGMP on cAMP-stimulated LH receptor expression in cultured granulosa cells.
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PMID:Roles of cyclic GMP in modulating ovarian functions. 1262 39

Soluble guanylyl cyclase (sGC) is activated by nitric oxide (NO) and carbon monoxide, resulting in cGMP production. Recent studies indicate that NO and cGMP influence ovarian functions. However, little information is available regarding the ovarian expression of sGC. The present study examined sGC alpha(1) and beta(1) subunit protein levels in the ovary during postnatal development, gonadotropin-induced follicle growth, ovulation, and luteinization as well as in cultured rat granulosa cells. In postnatal rats, sGC alpha(1) subunit immunoreactivity was high in granulosa cells of primordial and primary follicles on Day 5 but low in granulosa cells of larger follicles on Days 10 and 19. Theca cells of developing follicles, but not stromal cells, also demonstrated moderate sGC alpha(1) immunoreactivity. In gonadotropin- treated immature rats, intense sGC alpha(1) subunit staining was similarly observed in granulosa cells of primordial and primary follicles, but such staining was low in granulosa cells of small antral follicles and undetectable in granulosa cells of large antral and preovulatory follicles. Following ovulation, corpora lutea expressed moderate sGC alpha(1) immunoreactivity. Similar ovarian localization and expression patterns were seen for sGC beta(1), indicating regulated coexpression of sGC subunits. Immunoblot analysis revealed no change in total ovarian sGC alpha(1) and beta(1) subunit protein levels during gonadotropin treatment. Similarly, no effect of FSH on sGC subunit protein levels was apparent in cultured granulosa cells. These findings indicate regulated, cell- specific patterns of sGC expression in the ovary and are consistent with roles for cGMP in modulating ovarian functions.
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PMID:Cell-specific expression and regulation of soluble guanylyl cyclase alpha 1 and beta 1 subunits in the rat ovary. 1474

This study was conducted to evaluate the expression of endothelial nitric oxide synthase (eNOS) in ovarian follicles and corpora lutea (CL) throughout the estrous cycle in sheep. Three experiments were conducted to (1) immunolocalize eNOS protein, (2) determine expression of mRNA for eNOS and its receptor guanylate cyclase 1 soluble beta3 (GUCY1B3), and (3) co-localize eNOS and vascular endothelial growth factor (VEGF) proteins in the follicles and/or CL throughout the estrous cycle. In experiment 1, ovaries were collected from ewes treated with FSH, to induce follicular growth or atresia. In experiment 2, ovaries were collected from ewes treated with FSH and hCG to induce follicular growth and ovulation. In experiment 3, ovaries were collected from superovulated ewes to generate multiple CL on days 2, 4, 10, and 15 of the estrous cycle. In experiments 1 and 2, the expression of eNOS protein was detected in the blood vessels of the theca externa and interna of healthy ovarian follicles. However, in early and advanced atretic follicles, eNOS protein expression was absent or reduced. During the immediate postovulatory period, eNOS protein expression was detected in thecal-derived cells that appeared to be invading the granulosa layer. Expression of eNOS mRNA tended to increase in granulosa cells at 12 and 24 h, and in theca cells 48 h after hCG injection. In experiment 3, eNOS protein was located in the blood vessels of the CL during the estrous cycle. Dual localization of eNOS and VEGF proteins in the CL demonstrated that both were found in the blood vessels.
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PMID:Expression of endothelial nitric oxide synthase in the ovine ovary throughout the estrous cycle. 1700 69

Natriuretic peptide type C (NPPC) and its cognate receptor natriuretic peptide receptor 2 (NPR2) are essential for maintaining meiotic arrest in mouse oocytes residing in Graafian follicles. Cumulus cells, which are associated with the oocyte, express the receptor NPR2, a guanylyl cyclase, whereas mural granulosa cells express ligand NPPC. This study determined the temporal expression of Npr2 and the hormonal factors that participate in regulating its expression and, thereby, in oocyte meiotic arrest. Stimulation of follicular development in vivo with equine chorionic gonadotropin (eCG) promoted expression of Npr2 mRNA by cumulus cells and some periantral mural granulosa cells. However, FSH did not elevate the levels of Npr2 mRNA in cultured cumulus-oocyte complexes (COCs) isolated from mice not stimulated in vivo with eCG. Nevertheless, estradiol elevated expression of this transcript in vitro to the same steady-state level found in COCs isolated from eCG-stimulated follicles in vivo. Expression of Npr2 mRNA was rapidly reduced in COCs in vitro after isolation from eCG-primed mice unless maintained in culture with estradiol. The ability of NPPC to maintain meiotic arrest in cultured COCs was transient unless culture was in estradiol-containing medium. Ability of cumulus cells to produce cyclic GMP, which is required for the maintenance of meiotic arrest, was also lost in the absence of estradiol, indicating that estradiol is required to maintain functional NPR2 receptors on cumulus cells in vitro. It is concluded that estradiol promotes and maintains expression of NPR2 in cumulus cells and participates in NPPC-mediated maintenance of oocyte meiotic arrest in vitro.
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PMID:Estradiol promotes and maintains cumulus cell expression of natriuretic peptide receptor 2 (NPR2) and meiotic arrest in mouse oocytes in vitro. 2191 82


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