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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The follicle-stimulating hormone (FSH) receptor purified from calf bovine testis membranes appears to be an oligomeric glycoprotein, consisting of 4 disulfide-linked monomers of molecular weight about 60,000 each. Polyclonal antibodies to the hormone binding sites of the receptor have been developed. FSH interaction with the receptor seems to involve multiple discrete binding regions, which include amino acids 34-37 and 49-52 of the human FSH beta subunit. The interaction between FSH and the membrane-bound receptor is reversible at low temperatures but becomes increasingly irreversible as the temperature increases. FSH interaction with the soluble receptor is reversible over a wider temperature range. The hydrophobic effect is a significant factor in the initial hormone receptor interaction in each system. FSH bound to membrane receptors on cultured immature rat Sertoli cells is internalized and degraded to the level of amino acids. Current evidence suggests that the membrane receptor may exist as free receptor, and complexed with G-protein. A functional receptor/G-protein/adenylate cyclase complex has been reconstituted in liposomes. The G-protein of testis membranes contains both high and low affinity guanosine triphosphate (GTP) binding sites. Both are capable of modulating FSH receptor binding, whereas only the high affinity sites seem to be required for activation of adenylate cyclase. Although testis membranes contain a phosphatidylinositide hydrolysis system, the latter is not directly influenced by FSH.
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PMID:The follicle-stimulating hormone (FSH) receptor in testis: interaction with FSH, mechanism of signal transduction, and properties of the purified receptor. 249 20

In the fully grown Bufo arenarum oocyte, carbohydrate breakdown during the autumn-winter season is accomplished mainly through the glycolytic pathway followed by the Krebs cycle. During the breeding season (spring-summer), carbohydrates are used mainly through the pentose phosphate cycle and through the variant of the Krebs cycle known as the glutamic aspartic cycle. The metabolism operating in the oocytes was determined using the following parameters: 1) the capacity of isolated mitochondria to oxidize citrate and fumarate; 2) the enzymatic activities of phosphofructokinase (PFK) and glucose-6-phosphate dehydrogenase (G-6-PDH); and 3) citrate and ATP compartmentalization. The present paper shows that follicle-stimulating hormone (FSH) would be one of the factors responsible for summer metabolism, since ovary fractions obtained from winter specimens treated with the hormone acquired the metabolic characteristics corresponding to oocytes obtained from breeding-season animals. From dose-response, and response in the function of time curves, it could be assumed that the optimum doses and times were 0.1 micrograms FSH/ml of incubation medium and 30 min treatment, respectively. The metabolic effect of FSH upon oocytes could be mediated by the adenylate cyclase-cAMP system, since treatment of ovaric fractions with cAMP 10(-3) M reproduced the effects obtained with the hormone. In addition, 0.02 mg/ml tetracycline proved to block the effect of FSH. A direct metabolic action of FSH on body cavity oocytes (without follicle cells) was observed when submitting these oocytes to the same hormonal treatment.
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PMID:Effect of follicle-stimulating hormone on metabolism and maturation in Bufo arenarum oocytes. 250 14

High doses of phthalate esters in vivo cause testicular lesions. One initial target for these effects is the sustentacular Sertoli cell. Sertoli cells are unique in that they have surface membrane receptors for follicle-stimulating hormone (FSH), which couple to adenylate cyclase. As a means of investigating why phthalates appear specific for Sertoli cells, we evaluated possible effects of an active monoester [mono(2-ethylhexyl) phthalate, MEHP] on the ability of FSH to elevate intracellular levels of cAMP. MEHP reduced FSH-induced elevation of cAMP levels by approximately 40%. This inhibition by MEHP required a lag period of 6 hr and did not affect the dose of FSH which gave half-maximal stimulation, suggesting that MEHP does not compete with FSH for binding to its receptor. The MEHP inhibition was not affected by incubation in the presence of methylisobutylxanthine, a phosphodiesterase inhibitor, suggesting that MEHP does not stimulate the breakdown of cAMP. The MEHP-induced inhibition is specific for FSH; it does not affect the ability of forskolin, cholera toxin, isoproterenol, or prostaglandin E1 to stimulate Sertoli cell cAMP. Furthermore, inhibition occurs in the presence of pertussis toxin suggesting that MEHP action is independent of the inhibitory adenylate cyclase pathway. Further experiments will be necessary to define the specific mechanism of action of phthalates on Sertoli cells; however, these experiments do describe a specific site of action of MEHP in vitro which may be related to the in vivo testicular toxicity of phthalate esters.
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PMID:Inhibition of FSH-stimulated cAMP accumulation by mono(2-ethylhexyl) phthalate in primary rat Sertoli cell cultures. 253 9

Properties of a clonal line of SV40-transformed rat granulosa cells (DC3 cells) were elucidated. DC3 cells were maintained in vitro in Iscove Modified Dulbecco Medium that contained 20% fetal bovine serum. The cells had a logarithmic growth phase doubling time of approximately 18 h and produced detectable quantities of estrone, estradiol, and progesterone. Steroidogenesis was increased by supplementation with either steroidogenic substrates or agents that stimulated activity of adenylate cyclase. Production of progesterone and estrogens was enhanced when medium was supplemented with 25-hydroxycholesterol, and production of estradiol was enhanced by medium supplementation with androstenedione. Treatments with forskolin and cholera toxin resulted in marked increases of cyclic adenosine 3',5'-monophosphate (cAMP) in medium and cells and enhanced steroidogenesis. Isoproterenol and vasoactive intestinal peptide, but not follicle-stimulating hormone (FSH), luteinizing hormone (LH), insulin or prolactin, stimulated cAMP secretion by suspended cells. DC3 cells had small but detectable levels of binding to FSH, but binding of LH and epidermal growth factor could not be detected. DC3 cells possess characteristics expected of granulosa cells arrested in an early stage of differentiation and may provide a useful model for studies of "immature" granulosa cell functions.
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PMID:Physiologic characterization of transformed and cloned rat granulosa cells. 254 13

It has been suggested that resident ovarian macrophages may play a role in the regulation of ovarian function through local paracrine secretion of regulatory molecule(s). It is the objective of the in vitro studies reported herein to evaluate the potential ovarian relevance of one such macrophage product, tumor necrosis factor alpha (TNF-alpha). To this end, use was made of a primary culture system of rat ovarian granulosa cells, the functional status of which was monitored by the acquisition of estrogen, progestin, and proteoglycan biosynthetic capacity. Whereas treatment with the gonadotropin follicle-stimulating hormone (FSH), a potent functional regulator, resulted in a substantial increase in the extent of aromatization (conversion of androgenic steroid precursors to estrogens), concomitant exposure to TNF-alpha (10 ng/ml) produced significant (p less than 0.05), yet reversible inhibition (71 +/- 7%) of this FSH effect. This specific activity of TNF-alpha was characterized by a projected minimal effective dose of less than 0.1 ng/ml, an apparent median inhibitory dose of 0.56 +/- 0.14 ng/ml, and a minimal time requirement of 48 h. Significantly, the direct effect of TNF-alpha could not be accounted for by a decrease in cellular viability or plating efficiency, nor by a decrease in the number of cells or their DNA content. Instead, TNF-alpha inhibited FSH hormonal action at the level of stimulatable adenylate cyclase activity, exerting no apparent effect either at the level of the FSH receptor or at site(s) of action distal to cAMP generation. The effect of TNF-alpha was not limited to the attenuation of estrogen biosynthesis, exerting qualitatively similar effects on FSH-supported progestin and proteoglycan biosynthetic capacity. As such, these findings are in keeping with the notion that subnanomolar concentrations of TNF-alpha, possibly of ovarian macrophage origin, may comprise the signal of a paracrine loop designed to attenuate gonadotropin action thereby playing a potential role in the development and/or demise of the ovarian follicle.
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PMID:Tumor necrosis factor alpha inhibits gonadotropin hormonal action in nontransformed ovarian granulosa cells. A modulatory noncytotoxic property. 254 76

The "antigonadal" potential of the neurohypophysial hormones, previously demonstrated in vitro, was evaluated in vivo using hypophysectomized male rats. This approach minimizes the likelihood that the in vivo "antigonadal" effect of the neurohypophysial hormones may be due to their ability to attenuate the release of pituitary gonadotropins. Given that the identity of the putative endogenous occupant of testicular pressor-selective neurohypophysial receptors remains uncertain, use was made of a substitute probe, arginine vasotocin (AVT), the utility of which has been demonstrated in vitro. Concurrent in vivo treatment of follicle-stimulating hormone (FSH; 5 micrograms/rat/day)-maintained immature hypophysectomized rats with increasing doses of AVT (0.25-25 microgram/rat/day) produced significant (P less than 0.05) dose-dependent inhibition of the testicular luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor binding capacity (but not affinity; Kd = 1.8 X 10(-10) M) from 8.8 +/- (standard error; SE) 0.4 ng/testis to a level (3.2 +/- 0.2 ng/testis) lower than that of controls (64% reduction). This AVT-induced decrease in the testicular LH/hCG receptor content of FSH-maintained immature hypophysectomized rats was associated with significant (P less than 0.05) decrements in the hCG- and N6, 2'-O-dibutyryladeosine cyclic 3',5'-monophosphate [( Bu]2cAMP)-stimulated accumulation of 3 alpha-hydroxy-5 alpha-androstan-17-one (androsterone; 52% and 42% inhibition, respectively), with virtual elimination (98% inhibition) of the forskolin-stimulated accumulation of extracellular cAMP by testicular incubates in vitro, as well as with profound suppression of spermatogenesis. Taken together, these observations indicate that the "antigonadal" effect of the neurohypophysial hormones previously demonstrated in vitro, can be fully reproduced in vivo, and that the "antigonadal" activity of the neurohypophysial hormones may be accounted for, in large part, by decreased testicular LH/hCG binding capacity, stimulable adenylate cyclase activity, and cAMP-supported androgen biosynthesis.
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PMID:Antigonadal activity of the neurohypophysial hormones: in vivo regulation of testicular function of hypophysectomized rats. 282 23

Interactions between signal transducing systems may be important in the integrated control of cellular processes in basal and hormonally regulated cells. The swine granulosa cell provides a model to study the interactions between the cAMP and calcium-lipid-dependent signaling pathways. To this end, porcine granulosa cells were incubated in monolayer culture for 1-4 days in the presence of FSH (200 ng/ml), forskolin (85 microM), or cholera toxin (3 micrograms/ml) with or without an activator of protein kinase C, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) (30 ng/ml). TPA had little effect on basal cAMP generation (1-4 days) or on follicle-stimulating hormone (FSH)-stimulated cAMP formation during the first 24 h. Phorbol ester did inhibit cAMP formation on day 2 (by approximately 25%), on day 3 (by approximately 70%) and on day 4 (by greater than 80%). Forskolin-mediated cAMP generation was inhibited (33-56%) on days 1-4, respectively. TPA suppressed dose-dependent FSH (3-300 ng/ml)-stimulated cAMP production on day 2, virtually abolished FSH-provoked cAMP formation on day 4 and inhibited dose-dependent forskolin-stimulated cAMP production on both days. TPA had no effect on the half-maximally effective dose, ED50, of FSH-stimulated cAMP production but did decrease the ED50 of forskolin and the maximal stimulatory effect of FSH and forskolin on days 2 and 4. Similar effects were observed with the synthetic diacylglycerols DOG (1,2-dioctanoylglycerol) and OAG (1-oleoyl-2-acetylglycerol). The TPA effect was limited to the mammalian adenylate cyclase as it had no effect on bacterially derived adenylate cyclase from Bordetella pertussis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interactions of protein kinase C with receptor- and non-receptor-mediated cyclic AMP generation in swine granulosa cells. 284 82

Inhibitory (A1) adenosine receptors that attenuate adenylate cyclase activity are present in cultured Sertoli cells. To investigate the possible effect of activating these receptors on the secretion of inhibin by the Sertoli cell, immature rat Sertoli cells were incubated for 24 h with follicle-stimulating hormone (FSH) in the absence or presence of the non-metabolizable, adenosine agonist phenyl-isopropyl-adenosine (PIA), and the accumulation of alpha-inhibin immunoreactivity was measured in the medium. Although devoid of effects when added alone, PIA inhibited the FSH-dependent secretion of alpha-inhibin in a concentration-dependent manner (ED50 = 1-1.5 nM). PIA treatment of the Sertoli cells also rendered the cells less sensitive to FSH in terms of alpha-inhibin secretion. The concentration-response curve to FSH was shifted to the right when cells were incubated in the presence of 100-1000 nM PIA. In contrast, dibutyryl cAMP stimulation of alpha-inhibin accumulation was unaffected by treatment with PIA, indicating that the site of PIA action is at the level of cAMP synthesis. These data provide experimental evidence of adenosine modulation of inhibin secretion by the Sertoli cell and suggest that adenosine may act as a local modulator within the pituitary-testicular axis.
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PMID:Adenosine receptor-dependent modulation of inhibin secretion in cultured immature rat Sertoli cells. 284 85

Mono-(2-ethylhexyl)phthalate (MEHP) is one of a number of phthalate esters known to damage the rat testis with the Sertoli cell as its target. These effects can be modeled using primary testicular cell cultures. Stimulation of rat Sertoli cells by follicle-stimulating hormone (FSH) results in an increase in release of cAMP into the culture medium. However, cultures pretreated with MEHP (10(-7)-10(-4) M) showed a dose-related reduction in FSH-stimulated cAMP production (maximally greater than 50%), suggesting that MEHP is interfering with the FSH receptor-adenyl cyclase system. Detailed investigations of the system were conducted utilizing forskolin and choleratoxin, which both stimulate adenyl cyclase but bypass the FSH receptor to produce an increase in cAMP secretion. Cultures pretreated with MEHP (10(-9)-10(-5)M) showed no reduction in either forskolin- or choleratoxin-stimulated cAMP production. However, at low doses (10(-8)-10(-6)M) MEHP produced a potentiation (up to three times) of both forskolin- and choleratoxin-stimulated cAMP secretion, but gave slight inhibition at 5 X 10(-5) and 10(-4) M. These data indicate that MEHP produces a perturbation at the level of the FSH receptor, causing an inhibition of FSH action. This finding may be related to the age-dependent toxicity of the compound, since FSH is critical for the initiation of spermatogenesis in young animals, but is not necessary for the maintenance of spermatogenesis in adults. Thus an effect on FSH responsiveness in vitro may provide an indication of the mode of action of MEHP in vivo.
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PMID:Effect of mono-(2-ethylhexyl)phthalate on follicle-stimulating hormone responsiveness of cultured rat Sertoli cells. 284 63

Pre-incubation of rat Sertoli cells with concentrations of follicle-stimulating hormone (FSH) too low to stimulate plasminogen activator (PA) secretion, provoked an inhibition of its subsequent stimulation by an effective dose of the hormone. A kinetic study of this desensitization was performed using equine FSH (which exhibits prolonged stimulation of PA secretion) and porcine FSH (which like all other FSH tested, provokes a transient response). Low non-stimulating concentrations of both hormones were shown to inhibit the subsequent PA response to each of them. Desensitization of rat Sertoli cells by low (non-stimulating) concentrations of FSH did not modify the typical time course (transient or prolonged) of PA secretion under subsequent stimulation by porcine or equine FSH, respectively. Only the intensity of the response to each hormone was dramatically reduced. Besides, the induction of desensitization by these non-stimulating concentrations of FSH was shown to be very rapid (10-15 min). The precise mechanism of this desensitization is not yet clear but its abolishment by the cyclic nucleotide phosphodiesterase (PDE) inhibitor MIX is consistent with the hypothesis that activation of PDE occurs at lower FSH concentration than adenylate cyclase activation.
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PMID:Homologous desensitization of rat Sertoli cells by non-stimulating concentrations of follicle-stimulating hormone. 295 41


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