Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid-stimulating hormone (TSH) has been shown to stimulate mitosis in cultures of the continuous thyroid cell strain FRTL-5, and this system may be used to quantify the growth-promoting effects of thyroid stimulators. Removal of TSH from the culture medium led to a progressive decline in the metaphase index (MI) to zero, after 7 days. Thus the cell culture conditions may be manipulated so that metaphases are absent in control cultures, i.e. in the absence of TSH. Restimulation with TSH caused an increase in mitosis only after a lag-phase of 20-24 h. A maximum MI was observed between 40 and 50 h, with a secondary peak between 70 and 75 h. An immunoglobulin G (IgG) preparation from a thyrotoxic patient with a small goitre which was a potent stimulator of adenylate cyclase in these cells produced a similar time-course. A dose-response relationship to TSH was obtained 47 h after addition of the hormone. Significant stimulation was observed with 10 mu. TSH/l, and maximal stimulation with 1 unit TSH/l; the highest dose tested (10 units TSH/1) slightly decreased the MI below the maximum. Stimulation of these cells appeared to be TSH specific, since FSH, human chorionic gonadotrophin, LH and isoproterenol did not induce mitosis. Epidermal growth factor under the experimental conditions employed was unable to induce mitosis. However, an increase in mitosis was observed with the adenylate cyclase stimulator forskolin. These experiments confirm the mitogenic properties of TSH and we describe a metaphase index assay for the detection of thyroid growth promotors.
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PMID:Thyrotrophin stimulation of mitogenesis of the rat thyroid cell strain FRTL-5: a metaphase index assay for the detection of thyroid growth stimulators. 404 May 48

The beta 1-adrenergic receptor of rat Sertoli cells was characterized by measurement of the ability of adrenergic receptor agonists and antagonists to stimulate cAMP accumulation in Sertoli cells from 18-day-old rats. Epinephrine, norepinephrine and isoproterenol stimulate cAMP accumulation in Sertoli cells which is not additive with maximal doses of FSH and which is age-dependent, beta-antagonists, alprenolol, hydroxybenzylpindolol or propranolol inhibit isoproterenol-induced cAMP accumulation while alpha-adrenergic antagonists have no effect. Dobutamine and soterenol stimulated cAMP accumulation to a greater extent than albuterol and metoproterenol. Finally, the stimulatory effects of isoproterenol and zinterol are both more sensitive to inhibition by beta 1-antagonists than by beta 2-antagonists. Taken together these data indicate the presence of a beta 1-adrenergic receptor in Sertoli cells which is coupled to adenylate cyclase.
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PMID:Identification and characterization of a beta 1-adrenergic receptor in the rat Sertoli cell. 611 1

Unilaterally cryptorchid rats were examined at 3, 8, 15, 22 and 28 days after operation. There was a selective decrease in the adenylate cyclase (ATP pyrophosphate--lyase (cyclizing), EC 4.6.1.1) responses to gonadotrophin stimulation in the abdominal testis. This was associated with a parallel decrease in specific FSH and LH binding. There was no reduction in the response of testicular adenylate cyclases to prostaglandin (PG) E-1 or fluoride stimulation, indicating that both the GTP binding protein (N-component) and the catalytic subunit of the adenylate cyclase complexes were intact. The reduction in FSH-responsive adenylate cyclase activity in the abdominal testis was not due to a change in the Km for adenylate cyclase activation, but was due to a reduction in maximal velocities. Unilateral cryptorchidism was also associated with a rapid decline in soluble Mn2+-dependent adenylate cyclase activity in germ cells (spermatids). By 3 days after operation there was an 82% decrease in germ cell adenylate cyclase activity. The loss of soluble Mn2+-dependent adenylate cyclase activity was associated with a parallel decrease in Sertoli cell secretion of androgen binding protein, indicating that Sertoli cell factors may be important for the maintenance of germ cell adenylate cyclase activity. The desensitization of the gonadotrophin--responsive adenylate cyclases and the loss of gonadotrophin receptors in Leydig and Sertoli cells were not due to changes in plasma gonadotrophin values because LH concentrations were within normal limits and plasma FSH was only marginally elevated in the cryptorchid rats. No significant alterations of any of these parameters were seen in the scrotal testis of unilaterally cryptorchid rats when compared to values for intact controls.
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PMID:Changes in rat testicular adenylate cyclase activities and gonadotrophin binding during unilateral experimental cryptorchidism. 611 59

Granulosa cells isolated from immature Sprague-Dawley rat ovaries produce progesterone (31.7 pg/micrograms cell protein) in response to an acute FSH stimulus (5 micrograms/ml NIH-FSH-S11, 2 H). After culture for 48 h in the absence of hormones (control culture), progesterone production by the granulosa cells in response to FSH is significantly reduced (2.9 pg/micrograms cell protein). Cells cultured with prostaglandin E2 (PGE2, 1 microgram/ml) or dibutyryl-cAMP (dbcAMP, 1 mM) exhibited a discernibly greater steroidogenic response to FSH (12.5 and 53.4 pg/microgram cell protein, respectively) than that of control cultures. Therefore the presence of PGE2 or dbcAMP in the culture medium helps to maintain the steroidogenic capacity of granulosa cells in culture. It is probable that this capacity is maintained at a locus distal to the production of cAMP by FSH. Paradoxically, granulosa cells cultured with PGE2 produce less cAMP in response to FSH stimulation than cells in control cultures (15.9 vs. 250.3 fm/micrograms cell protein). This may be due to a suppressive effect of prior exposure to PGE2 on the subsequent activity of adenylate cyclase when the FSH is introduced and a concomitant elevation of phosphodiesterase activity.
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PMID:PGE2 and dibutyryl-cAMP enhance the response of rat granulosa cells to FSH. 618 48

Deglycosylated LH ( DGLH ) abolished the stimulatory effect of LH on cAMP production by mature granulosa cells. DGLH , however, had no such inhibitory effect on the stimulatory activity of FSH, prostaglandin E2, isoproterenol, or choleragen. We have examined whether DGLH could prevent the desensitization of the cAMP response induced by continuous exposure to LH, or if it would induce receptor down-regulation. Cells were cultured with DGLH and LH concomitantly for a period of 3 h or 20 h and afterwards washed in acidic medium to dissociate bound ligands from their receptors. The cells were then challenged with fresh LH or with labeled 125I-human CG. At 20 h of culture with LH the cAMP response to the LH challenge was only 10% of the control, whereas after a 20-h culture with DGLH there was a 55% response to challenge with LH. DGLH , however, prevented LH from inducing desensitization in a dose-dependent manner (0.2-1.0 microgram/ml). Both LH and DGLH (1.0 microgram/ml each) markedly reduced (85%) the extent of binding of 125I-human CG to membrane receptors. At 3 h of culture, the cAMP response to challenge with LH was 25% of the control, whereas after 3-h culture with DGLH there was a 65% response to challenge with LH. DGLH (1.0 micrograms/ml) again prevented LH-induced desensitization, although only a moderate reduction in receptor-binding capacity (33%) by LH or DGLH was noted. The results suggest that occupancy of LH receptors alone for a long period is essential, but not sufficient to induce hormone desensitization. DGLH on its own is as active as LH in inducing a loss of membrane receptors, but causes only a moderate desensitization. The data support previous evidence that desensitization may result from postreceptor events, such as uncoupling of the receptors from the adenylate cyclase moiety, rather than receptor disappearance.
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PMID:Deglycosylated luteinizing hormone (LH) prevents desensitization of cyclic adenosine monophosphate response by LH: dissociation between receptor uncoupling and down-regulation. 620 97

The effect of forskolin (an adenyl cyclase activator) and 1-methyl-3-isobutylxanthine (MIX, a phosphodiesterase inhibitor) on granulosa cell steroidogenesis and LH receptor formation was studied in vitro. Granulosa cells from immature hypophysectomized, estrogen-treated rats were cultured for 2-3 days in androstenedione-supplemented media in the absence or presence of FSH or forskolin (10(-7)-10(-4) M). Some cultures were also treated with forskolin with or without MIX (0.125-1.0 mM) or theophylline (1.25-10 mM). Forskolin (3 X 10(-6)-10(-4) M) stimulated the production of estrogen, progesterone, 20 alpha-hydroxypregn-4-en-3-one (20 alpha-OH-P) and cAMP in a dose-related manner to levels similar to or higher than that elicited by FSH alone. Similarly, forskolin and FSH both increased LH/hCG receptor content in cultured granulosa cells, although forskolin was only 50% as effective as FSH. Treatment with MIX alone increased basal levels of cAMP, accompanied by elevations of estrogen and progestin biosynthesis without affecting LH/hCG receptor content. In contrast, theophylline treatment only increased cAMP and progestin accumulation. Furthermore, MIX potentiated the stimulatory effects of forskolin and FSH on cAMP and progestin production. In contrast, MIX inhibited FSH- and forskolin-stimulated estrogen production. Thus, activation of adenyl cyclase and inhibition of cAMP breakdown in the cultured rat granulosa cells enhance steroidogenesis and LH receptor formation, reinforcing the concept that cAMP is a (but may not be the only) second messenger in the hormonal regulation of granulosa cell differentiation.
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PMID:Forskolin and phosphodiesterase inhibitors stimulate rat granulosa cell differentiation. 620 17

Carp gonadotropin (cGTH) stimulated adenylate cyclase from 20-24 day old (but not 16-18 day old) rat ovaries; its subunits were inactive. Carp GTH (but not its subunits) increased the apparent KD for oFSH but not for oLH. These results suggest that cGTH mainly interacts with FSH sensitive adenylate cyclase-receptor systems, with an efficiency about 6 X 10(3) times lower than oFSH itself.
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PMID:[Effects of a gonadotropic hormone of teleost fish on the adenylate cyclase of rat ovary and on its stimulation by ovine gonadotropins]. 622 Jul 87

Treatment of purified rat ovarian plasma membranes with N,N'-dicyclohexylcarbodiimide (DCC) abolishes the subsequent response of adenylate cyclase [EC 4.6.1.1, ATP pyrophosphate lyase (cyclizing)] to lutropin (LH) and follitropin (FSH) but not to NaF. Such treatment also inhibits binding to these membranes of iodinated [125I] human chorionic gonadotropin (125I-hCG). Preincubation for 30 min at room temperature with 70 microM DCC reduces the response of adenylate cyclase to LH by 50% whereas 4 times higher concentration is required to reduce 125I-hCG binding to the same extent. At 0.5 mM, DCC reduces both activities by 50% within 8-10 min. Preincubation of the membranes with hCG prior to treatment with DCC protects the hormone-binding site of the receptor but not the ability of the enzyme to respond to LH. Thus the enzyme becomes functionally uncoupled. It is suggested that at least two distinct sites in the enzyme system are affected by DCC. Both sites are located proximal to the regulatory step that involves GTP-binding protein. One site seems to be associated with the receptor and the second is located distal to receptor-hormone complex formation.
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PMID:Uncoupling of gonadotropin-sensitive adenylate cyclase by N,N'-dicyclohexylcarbodiimide. Evidence for modification of two sites. 624 96

Immature female rats that had been primed with pregnant-mare serum gonadotropin (PMSG) were injected intravenously with various doses of human choriogonadotropin (hCG) for the investigation of the relationship between adenylate cyclase activities and the concentrations of LH/hCG receptor in luteinizing granulosa cells. Injection of 1 microgram of hCG induced a loss of LH and FSH sensitivities of adenylate cyclase within 6 h and a disappearance of free LH/hCG receptors within 24 h. Basal adenylate cyclase activity has a transient maximum at 6 h after hCG injection. After injection of 100 micrograms of hCG the loss of LH sensitivity of adenylate cyclase and free LH/hCG receptors occurred immediately, but the changes in FSH-stimulated and basal activities followed the same time scale as after injection of 1 microgram of hCG. When hCG was omitted from the injections the response of the animals to the endogenous gonadotropin surge varied. A complete desensitization of adenylate cyclase to LH and FSH stimulation and a 65% loss of free LH/hCG receptors were found at 24 h if the follicles were ovulated. These results suggest that occupation of a limited number of LH/hCG receptors in granulosa cells induces adenylate cyclase refractory to further stimulation by gonadotropins. The transient elevation of basal adenylate cyclase activity and its desensitization to further stimulation by gonadotropins may have a role in physiological processes leading to ovulation and luteinization.
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PMID:Human choriogonadotropin-induced desensitization of granulosa-cell adenylate cyclase to gonadotropins and loss of LH/hCG receptor. 625 22

TSH receptor and adenylate cyclase activity of plasma membrane fractions of human thyroid tumors were examined. The mean (+/- SD) basal adenylate cyclase activity in normal thyroid tissues was 0.35 +/- 0.33 nmole/mg protein x 10 min. The activity rose to 280% (range, 270-310%) of basal with TSH (166 mU/ml). In adenomas, the activity rose to 600% (range, 530-650), which was significantly higher than that of normal thyroid (P < 0.005). In the differentiated carcinoma, TSH responsiveness of adenylate cyclase was heterogenous (range, 110-520), but was qualitatively similar to that of the normal thyroid. On the other hand, basal adenylate cyclase activity of undifferentiated carcinoma was significantly lower than that of normal thyroid (0.018 +/- 0.007 nmol/mg protein x 10 min; P < 0.05) and was not stimulated by TSH. LH, FSH, and ACTH did not stimulate the enzyme in either kind of carcinomas. The mean (+/- SD) of the capacity of the high affinity receptor of adenomas (0.72 +/- 0.64 pmol/mg protein) and differentiated carcinomas (0.77 +/- 0.84) was not significantly different from that of normal thyroid (0.92 +/- 0.84). The affinity constants of the receptors in these three tissues were much the same (1.6-2.4 x 10(10) M-1). On the other hand, high affinity receptor could not be detected in all of the undifferentiated thyroid carcinoma. It seems likely that the failure of adenylate cyclase to respond to TSH in undifferentiated carcinoma of the thyroid is due to an alteration at the level of the receptor site. These data suggest that growth and metabolic activity of undifferentiated carcinoma may be independent of TSH, while those of adenoma and differentiated carcinoma may be affected by TSH.
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PMID:Thyrotropin (TSH) receptor and adenylate cyclase activity in human thyroid tumors: absence of high affinity receptor and loss of TSH responsiveness in undifferentiated thyroid carcinoma. 625 3


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