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)

Luteinizing hormone is the major regulator of Leydig cell differentiation and steroidogenic function. A number of hormones produced by the Leydig cell (e.g. estrogen, angiotensin, CRF, vasopressin) and the tubular compartment (inhibin, TGF beta), can influence both acute and long-term actions of LH. Conversely, hormones produced in the Leydig cells modulate tubular function (e.g. androgen, beta-endorphin, oxytocin). The LH stimulatory event can be negatively influenced by the action of angiotensin II through the guanyl nucleotide inhibitory unit of adenylate cyclase. We have recently discovered an action of corticotrophin releasing hormone through specific high-affinity low-capacity receptors in the Leydig cells which involves a pertussis toxin insensitive guanyl nucleotide regulatory unit with interaction between signalling pathways and resulting inhibition of LH induced cAMP generation and consequently of steroidogenesis. In contrast to other tissues the CRF receptor in the Leydig cells did not couple to Gs. CRF action is exerted through direct or indirect action of protein kinase C, at the level of the catalytic subunit of adenylate cyclase. Physiological increases in endogenous LH cause positive regulation of membrane receptors and steroidogenesis, while major elevations in circulating gonadotropin can induce down-regulation of LH receptors and desensitization of steroid responses in the adult cell. Gonadotropin-induced desensitization in adult rat tests include an estrogen mediated steroidogenic lesion of the microsomal enzymes 17 alpha-hydroxylase/17,20-desmolase. For further understanding of the regulation of this key enzyme of the androgen pathway the rat P450(17) alpha cDNA was cloned and sequenced. This cDNA expressed in COS-1 cells 17 alpha-hydroxylase/17,20-desmolase activities. From the deduced amino acid sequence, two transmembrane regions were identified, a signal peptide for insertion in the ER, and a 2nd transmembrane region separated from the first by 122 amino acids. The carboxy terminal non-transmembrane region possesses 4 hydrophobic clefts, of which cleft II would contain the putative steroid binding site for both hydroxylase and lyase activities. The rat cDNA was employed to evaluate the hormonal regulation of mRNA levels in adult and fetal Leydig cells. Low dose hCG treatment caused an early increase in mRNA levels followed by a return to control values at later times, while with higher desensitizing doses the initial increase in mRNA was followed by a marked reduction in mRNA at 24 h and a small recovery at 48 h. Fetal rat Leydig cells treated with E2 showed a 70% decrease in P450 mRNA levels, and testosterone production closely followed the changes in mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:LH action in the Leydig cell: modulation by angiotensin II and corticotropin releasing hormone, and regulation of P450(17) alpha mRNA. 269 45

The influence of follicular maturation on progesterone production by collagenase-dispersed hen granulosa cells was measured in short-term incubations. Granulosa cells of the largest follicle (F1) produced up to ten times more progesterone than cells from smaller follicles (F3-F5), not only in response to luteinizing hormone (LH), but also when stimulated by exogenous cyclic AMP or forskolin, both of which raise intracellular cyclic AMP levels by nonreceptor-mediated mechanisms. Moreover, when granulosa cell progesterone synthesis was stimulated by incorporating 25-hydroxy-cholesterol into the incubation medium, an identical pattern was obtained. This could be attributed to a corresponding increase in the specific activity of the mitochondrial cholesterol side-chain cleavage enzyme (20,22 desmolase). An increase in the apparent Vmax was observed without a change in the apparent Km values. Pregnenolone substrate at concentrations which raised progesterone production to levels similar to those observed in response to LH stimulation was utilized equally by granulosa cells of mature and developing follicles. However, at high pregnenolone concentrations, granulosa cells of mature follicles converted significantly more of the precursor to progesterone. Assay of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) showed that the enzyme has two Kms: a low Km present in cells of both mature and developing follicles, and a high Km found only in granulosa cells of more mature follicles. It is concluded that LH-promoted progesterone synthesis in granulosa cells of developing chicken follicles is restricted not so much by the availability of receptors and the competence of the adenylate cyclase/cyclic AMP system, but by the activity of key enzymes, principally the cholesterol-20,22 desmolase.
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PMID:Influence of follicular maturation on luteinizing hormone-, cyclic 3',5'-adenosine monophosphate-, forskolin- and cholesterol-stimulated progesterone production in hen granulosa cells. 298 34

The conversion of cholesterol to pregnenolone by adrenocortical mitochondria is the rate-limiting step in steroidogenesis. This process is stimulated dramatically by the action of ACTH through the sequential reactions, in which adenyl cyclase, cAMP-dependent protein kinase, cholesterol esterase and ribosomal protein synthesis are all involved. The de novo synthesized protein, the so-called labile protein with a half-life of approx 10 min, is believed to stimulate the cholesterol side chain cleavage reaction by an unknown mechanism. Available evidence indicates that the electron on transfer reaction from NADPH to P-450scc is mediated rapidly by adrenodoxin reductase and p-450 scc. In addition, these redox components are inactivated slowly with a half-life of 3.5 days after hypophysectomy. It is known that the corticoid output from adrenocortical cells starts within 5 min and reaches the maximum after 10-15 min of ACTH administration to animals. One can assume that under normal physiological conditions, both O2 and NADPH are not limiting. Additionally, mitochondrial inner membranes are poor in cholesterol. In this context, the availability of substrate cholesterol to P450scc is the most likely candidate for the regulatory mechanism.
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PMID:Transduction of ACTH signal from plasma membrane to mitochondria in adrenocortical steroidogenesis. Effects of peptide, phospholipid, and calcium. 302 55

Output of progesterone, the end product of the steroidogenic pathway, was studied in isolated chicken granulosa cells in relation to follicular maturation and during the ovulation cycle with particular reference to the period between the LH peak and ovulation. The evidence gathered from a series of experiments conducted during the past 2-3 years in the authors' laboratory indicate that the steroidogenic capacity of granulosa cells during follicular maturation is regulated not so much by receptor-coupled adenylate cyclase activity as has been proposed by other investigators, but by the activity of key steroidogenic enzymes, particularly the cholesterol 20,22 desmolase. Furthermore, granulosa cells undergo cyclic sensitization following the endogenous LH surge reaching maximal responsiveness about 1 hr before oviposition. This is followed by a rapid desensitization shortly before ovulation. This desensitization extends to the second and subsequent developing follicles probably in proportion to the evolving LH receptors. It is suggested that granulosa cells remain in such a desensitized state for several hours postovulation, during which time progesterone responses to LH are attenuated and consequently ovulation does not occur prematurely. It is proposed that this intraovarian mechanism is an important component of the physiological events that regulate the ovulation cycle in the domestic fowl.
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PMID:Steroidogenesis in granulosa cells during follicular maturation: evidence for desensitization-resensitization during the ovulation cycle. 609 32

Adrenal cortical mitochondria contain a mixed function oxidase capable of converting cholesterol to pregnenolone; this enzyme requires NADPH, oxygen and cholesterol. This cholesterol side chain cleavage enzyme system contains a Flavoprotein, an iron sulphur protein and a specific cytochrome P450 termed cytochrome P450scc. ACTH stimulates the adrenal cortex by activating adenyl cyclase producing an elevated intracellular concentration of cAMP. This in turn increases the activity of a cytosolic cAMP dependent protein kinase. Adrenal cortical cytosol contains a cholesterol ester hydrolase which is activated by ATP and a protein kinase. This enzyme may be deactivated by a phosphoprotein phosphatase. The adrenal cortex contains lipid droplets that are rich in esterified cholesterol. Cholesterol ester hydrolase can release free cholesterol from the lipid droplets. The free cholesterol released may be used to supplement the mitochondrial cholesterol as a pregnenolone precursor. Steroid hormone production by the adrenal cortex exhibits a diurnal rhythm and correlates with the activity of the cytosolic cholesterol ester hydrolase. The acute steroidogenic response to ACTH may be in part attributed to the availability of free cholesterol to the mitochondrial cholesterol side chain cleavage enzyme complex. The intracellular movement of free cholesterol from lipid droplets to mitochondrial inner membranes may be impeded by protein synthesis inhibitors such as cycloheximide. The precise mechanism of this block in steroidogenesis remains to be elucidated. Various drugs and oestrogenic hormones suppress the plasma and adrenal cholesterol concentrations. If adrenal cells are deficient in cholesterol, these cells exhibit a diminished response to ACTH. The response to this hormone can be corrected by supplying cholesterol via exogenous plasma lipoproteins. The route that free cholesterol follows within the adrenal cortical cell and the physiological factors influencing free cholesterol movement in such cells are important issues to be explored in future.
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PMID:Cholesterol metabolism in the adrenal cortex. 631 Feb 52

The control of androgen production by the Leydig cell is dependent upon the episodic secretion of hormone (LH), which is released from the anterior pituitary gland in pulses of high biological activity. This mode of episodic LH secretion supports steroidogenic enzyme activity in the testis through interaction with LH receptors and stimulation of the adenylate cyclase/protein kinase sequence, leading to phosphorylation of key intermediates in the steroid biosynthetic pathway. The plasma membrane events that are rapidly activated by the specific interaction of LH or hCG with Leydig cell receptors include increased binding of guanyl nucleotide, and stimulation of cAMP-independent, Ca2+-dependent phosphorylation of a 44,500 Mr protein, with the characteristics of the adenylate cyclase nucleotide regulatory unit. Hormonal activation of adenylate cyclase is affected by Ca2+ with the same concentration-dependence, suggesting that nucleotide-induced phosphorylation is related to activation of the catalytic cyclase unit. In addition to the characteristic increases in pregnenolone synthesis and androgen production, gonadotropin-stimulated Leydig cells show prominent changes in LH receptor content and steroidogenic activity that modify their subsequent responses to hormonal signals. Thus, after exposure to increased LH and hCG levels in vivo and in vitro, LH receptors show an initial transient increase (up-regulation) followed by a marked decrease (down-regulation) and a prolonged depletion of LH receptor sites. Large doses of hCG cause "early" (prior to pregnenolone) and "late" steroidogenic lesions (17 alpha-hydroxylase, 17-20 desmolase) that are independent of receptor loss. The early lesion is partly due to reduced activity of HMG CoA reductase, and is mainly attributable to the increased activity of an inhibitory protein factor that modulates the activity of cholesterol side chain cleavage enzyme in Leydig cell mitochondria. In contrast, the late steroidogenic lesion is related to the nuclear actions of E2 produced during hormonal action. After hCG stimulation, an increase in nuclear E2 binding was accompanied by an early rise of RNA polymerase activities within 45 min coincident with the maximal increases in circulating testosterone and estradiol levels. These events were followed by the emergence of an E2-induced protein of Mr 27,000 at 3-6 h, and by reduction in the activity of 17 alpha-hydroxylase/17-20 desmolase, and a decrease in microsomal cytochrome P-450.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hormonal regulation of androgen production by the Leydig cell. 632 62

The series of events, evidenced in animals after a single injection of human chorionic gonadotrophin (hCG): down-regulation of LH/hCG membrane receptors, uncoupling between receptors and the adenylate cyclase, also includes a blockade of testicular steroidogenesis beyond cyclic-AMP formation, including an inhibition of the 17 alpha-hydroxylase-17, 20-desmolase enzymatic complex. This complex phenomenon, named hCG-induced testicular desensitization also occurs in adult men. Since it is not known if and when these effects are initiated during sexual maturation, we have investigated the kinetics of responses of plasma testosterone (T), its two immediate precursors, delta 4-androstenedione (delta 4) and 17 alpha-hydroxprogesterone (OHP), and 17 beta-estradiol (E2) for a week after a single injection of hCG given at the same dosage (100 IU/kg body weight) in subjects not yet exposed to adult levels of endogenous LH, ie prepubertal boys and untreated hypogonadotrophic hypogonadic (HH) adult men. The HH subjects have been restudied after 3 months of a weekly injection of the hCG at the same dosage. In immature individuals, the effect of hCG on testicular steroidogenisis was strikingly different from that observed previously in adults: in the former, whether prepubertal boys or untreated HH adults, a single hCG injection induced a progressive and substantial rise in plasma T, maximal at 96-120 h, a modest and late rise in E2, but no significant change in delta 4 or OHP. In contrast, in adult men there is a dissociation between the responses of plasma T and delta 4 (maximal at about 72 h) to hCG and those of OHP and E2 which peak at about 24 h. After 3 months of hCG-treatment the adult pattern was induced in HH patients: early and significant rise in OHP and E2. This suggests that a pre-exposure to LH/hCG is necessary for hCG-induced testicular desensitization, at least for its enzymatic expression. A stimulatory effect of hCG on a testicular aromatase and an inhibitory effect on the 17, 20-desmolase are observed concomitantly in relation to age or to previous gonadotropin environment. It still remains uncertain to conclude that the former effect is directly responsible for the latter.
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PMID:[Kinetics of the steroidogenic response of the testis to stimulation by hCG. V. Blockade of 17-20 lyase induced by hCG is an age-dependent phenomenon inducible by pre-treatment with hCG]. 653 46

The effects of melatonin (MLT; 4.3 pM to 4.3 microM) on rat Leydig cell steroidogenesis and cAMP production were investigated during 3-h LH (30 mIU/ml) stimulation. Having noted a dose-dependent inhibition of testosterone (T) release, we also tested MLT in the presence of the cAMP activator forskolin (1 microM), the phosphodiesterase inhibitor isobutylmethylxanthine (100 microM), a combination of these two, and LHRH (100 nM), a non-cAMP-mediated stimulus. Regardless of the stimulus, levels of T, androstenedione, and cAMP were reduced, whereas that of 17-hydroxyprogesterone was enhanced. Cells were also tested after prolonged exposure to MLT (215 nM for 16 h). When compared with data from cells not preincubated with MLT, cAMP and T levels were 30% higher during LH stimulation (30 mIU/ml); comparable during treatment with forskolin (1 microM), isobutylmethylxanthine (100 microM), or their combination; and reduced during LHRH (100 nM). Scatchard analysis did not reveal changes in LH receptors during prolonged MLT exposure. Our data show that MLT acutely reduces cAMP- and non-cAMP-stimulated T. This effect is linked in part to reduced cAMP production and in part to reduced 17-20-desmolase enzymatic activity, which, however, can occur even with non-cAMP-mediated stimulation. On the other hand, prolonged exposure to MLT results in sensitization of the LH-dependent adenylate cyclase activity.
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PMID:In vitro acute and prolonged effects of melatonin on purified rat Leydig cell steroidogenesis and adenosine 3',5'-monophosphate production. 758 82

Virilizing adrenal tumours, adenomas and adenocarcinomas are rare and their clinical manifestations vary depending on age at onset. The paper reports the results obtained in 4 patients with adenoma and 3 with adenocarcinoma, as well as 11 cases of classic congenital adrenogenital syndrome by way of comparison. The hormonal status of adenomas is usually characterised by a predominant increase in plasma androstenedione (> 600, ng/dl) and testosterone (> 200 ng/dl), whereas carcinomas present a predominant hypersecretion of dehydroepiandrosterone (> 1200 ng/dl) and its sulphate (> 700 micrograms/dl). Plasma estrogen levels may also be enhanced due to active peripheral androgen conversion or direct secretion. 17alpha-hydroxyprogesterone, which is high in congenital adrenal hyperplasia, is normal or slightly enhanced, as is cortisol. Differential diagnosis must be made with androgen secreting tumours of the ovaries and, in males, with the various forms of precocious puberty, including endocrine tumours of the testicle, as well as congenital adrenogenital syndrome. A tumour with a diameter > 7 cm when examined using CT or NMR may be suspected as carcinoma, but malignancy cannot be excluded even in smaller tumours. Virilizing adrenal tumours do not usually respond to dexamethasone suppression test or ACTH stimulus since they do not express ACTH receptors or present post receptor anomalies. Steroidogenesis may be cAMP/protein-kinase independent and can be activated through alternative pathways. The presence of a stimulating G-protein has been detected in carcinomas which serves to activate adenylate cyclase on a permanent basis. b6 cytochrome is super-expressed and may be responsible for androgen over-secretion by activating 17,20-desmolase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Androgen-secreting adrenal tumors. 765 Dec 84

In previous studies in porcine granulosa cell cultures, endothelin-1 (ET-1) was shown to inhibit FSH-stimulated cAMP and progesterone accumulation, and to increase inositol phosphate formation and cytosolic calcium ion concentration. The latter results suggest an action of ET-1 via the activation of phospholipase C. Here we have investigated the following experimental questions. (1) Does ET-1 activate PKC in ovarian cells? (2) Does the cellular mechanism(s) whereby ET-1 interferes with the steroidogenic action of FSH in granulosa cells involve an impairment of cAMP generation or action? And (3) how does the site(s) of the inhibitory effect(s) of ET-1 and TPA on FSH-stimulated progesterone accumulation in cultured granulosa cells compare? In the present investigation, ET-1 (1 microM) induced rapid cytosol-to-membrane translocation of [3H]phorbol 12,13-dibutyrate binding sites, indicating protein kinase C (PKC) activation. At 24 or 48 h, ET-1 inhibited FSH-, but not forskolin (1 microM)-induced, cAMP accumulation. Cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) messenger RNA (mRNA) accumulation was stimulated by FSH, 8-bromo-cAMP (8Br-cAMP, 0.5 mM) and forskolin. ET-1 significantly inhibited this effect of FSH, but not the effects of 8Br-cAMP and forskolin. Progesterone production decreased commensurately with this inhibitory action of ET-1 on the FSH-stimulated accumulation P450scc mRNA. The PKC activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), suppressed steroidogenesis stimulated by forskolin and 8Br-cAMP as well as FSH. In conclusion, ET-1 inhibited FSH-stimulated cAMP accumulation, P450scc expression, and progesterone production in porcine granulosa cell cultures. The data are compatible with pre-adenylate cyclase site of action. Although ET-1 activated PKC, TPA, unlike ET-1, seems to inhibit steroidogenesis by interfering with cAMP action.
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PMID:Mechanisms underlying endothelin's inhibition of FSH-stimulated progesterone production by ovarian granulosa cells. 1061 35


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