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)

The effects of spent media from seminiferous tubules (STM) on Percoll-purified rat Leydig cells were investigated. Intracellular and extracellular cyclic AMP (cAMP) accumulation and testosterone production were measured. After a 5 h incubation period, STM reduces both the basal and LH-dependent cAMP levels (38 and 20%, respectively for intra- and extracellular cAMP) while, simultaneously, a stimulation of testosterone production is observed (47 to 50%, respectively in the absence or presence of LH). The reduction of cAMP levels observed after 5 h is likely to be due to the potentiating effect of the STM factor on the LH-dependent initial rise of the cAMP level which, in turn, induces a desensitization of the Leydig cell adenylate cyclase. This substance is a thermolabile protein (Mr greater than 50 000) produced by the Sertoli cell, independent of FSH and testosterone controls, and different from the LHRH-like substance.
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PMID:Effects of seminiferous tubule secreted factor(s) on Leydig cell cyclic AMP production in mature rat. 301 82

Adult rat Leydig cell aromatase activity is stimulated 2.5 fold by LH or dbcAMP. Spent media prepared from seminiferous tubules or Sertoli cells of immature rats depress both the basal and the LH stimulated estradiol syntheses (25 and 20% decreases, respectively). These inhibitory effects are further enhanced when FSH is added to the culture medium of seminiferous tubules or Sertoli cells. Rat serum as well as culture media from other cell lines are ineffective while seminiferous tubule media from other immature animals (mouse, guinea-pig, calf) inhibit the aromatase activity. This Sertoli cell factor is a heat stable protein (molecular weight greater than 10 kDa), different from the LHRH-like Sertoli cell compound, which acts on the aromatase activity at a step beyond the adenylate cyclase.
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PMID:Spent media from immature seminiferous tubules and Sertoli cells inhibit adult rat Leydig cell aromatase activity. 303 Sep 13

Activation and regulation of Leydig cell function is exerted primarily by LH, which is secreted in pulses of high biological activity and interacts with membrane receptors. Other hormones and factors secreted by the Leydig cell or from the tubular compartment can influence Leydig cell differentiation and acute or chronic actions of LH on steroidogenesis. Conversely, hormones produced in the Leydig cell could modulate tubular function (e.g. beta-endorphin, oxcytocin). The LH receptor has been purified to homogeneity in sufficient quantities to allow its peptide sequence to be determined and its gene structure to be elucidated as well as functional reconstitution studies to be performed. The LH receptor subunit of Mr 90,000 can be phosphorylated by cAMP-dependent protein kinase. The native receptor appears to exist in the membrane as a dimer of identical subunits associated by noncovalent interactions. It is likely that receptor dimerization and further aggregation are necessary for signal transduction to occur, and receptor phosphorylation by one or more kinases may be involved in regulating gonadotropin action. Stimulation of the androgen pathway occurs mainly through a cAMP-mediated mechanism. The stimulatory event can be negatively influenced by the action of certain peptide hormones through the guanyl nucleotide inhibitory subunit of adenylate cyclase. Such an inhibitory action of angiotensin has further emphasized the importance of the cAMP pathway in the Leydig cell. The hormone also appears to facilitate androgen production by a cAMP-independent mechanism located at the plasma membrane or intracellular sites. A Ca2+ sensitive kinase system is present in the Leydig cell membranes. The presence of nM amounts of Ca2+ induces membrane phosphorylation of a protein Mr 45,000. Adenylate cyclase activation also is affected by Ca2+. Membrane phosphorylation may be a modifier of LH-stimulated adenylate cyclase activity and possibly other LH-induced actions in the activated Leydig cell membrane. In the adult rat testis, the ability of Leydig cells to respond to sustained gonadotropic stimulation with increased androgen production is limited by the development of a refractory state associated with loss of LH receptors and steroidogenic enzymes. Gonadotropin-induced steroidogenic lesions in adult rat testes include a late steroidogenic lesion at the site of conversion of progesterone to androgen and an early lesion before pregnenolone formation that leads to a decreased in vitro pregnenolone and testosterone response to hCG.
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PMID:Endocrine regulation and communicating functions of the Leydig cell. 328 2

The receptor binding properties and biologic actions of chemically deglycosylated-asialo human choriogonadotropin (AHF-hCG) were studied in human ovary and testis. In corpus luteum and testis homogenates, the relative binding affinity of AHF-hCG was two- to fourfold higher in the ovary and five- to tenfold higher in the testis than that of native hCG. When assayed for luteinizing hormone (LH)-like activity in granulosa-luteal cells from in vitro fertilization patients and in testicular minces from patients undergoing orchiectomy for prostatic cancer, AHF-hCG did not stimulate cyclic adenosine monophosphate production. When added with hCG to granulosa-luteal cells or to testicular minces, AHF-hCG inhibited hCG-stimulated cyclic adenosine monophosphate production. These results indicate that the enhanced affinity to LH receptor caused by removal of the sugar moieties from hCG is associated with total inability to activate granulosa-luteal and Leydig cell adenylate cyclase, and that AHF-hCG is, in the human gonad, an hCG antagonist.
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PMID:Receptor binding properties and biologic action of deglycosylated human chorionic gonadotropin in human ovary and testis. 360 Dec 78

Production of testosterone and oestradiol-17 beta by Leydig cells from adult rats was stimulated by LH or dibutyryl cyclic AMP (10 and 2.5-fold respectively). The addition of spent medium from normal, hemicastrated or gamma-irradiated rat seminiferous tubule cultures, as well as from Sertoli cell cultures, to purified Leydig cells further enhanced both basal (44 and 53% for testosterone and oestradiol-17 beta respectively) and LH-stimulated (56 and 18%) steroid output. Simultaneously, a decrease (20-30%) in intracellular cyclic AMP levels was observed. This stimulating factor (or factors) secreted by the Sertoli cells is different from LHRH, is of proteinic nature and has a molecular weight ranging between 10,000 and 50,000; its synthesis is not controlled by FSH nor by testosterone. This factor(s) involved in rat Leydig cell steroidogenesis, at a step beyond the adenylate cyclase, does not require protein synthesis for testosterone formation whereas it does for oestradiol-17 beta production. It should be noted that a germ cell-Sertoli cell interaction modulates the synthesis of this factor(s).
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PMID:Adult rat Sertoli cells secrete a factor or factors which modulate Leydig cell function. 366 35

Key reactions associated with the capacity of the isolated Leydig cell to synthesize testosterone were studied in male rats acclimatized to a hot environment (33-35 degrees C, 25-40% relative humidity) and controls (20-22 degrees C, 30-50% relative humidity). The results demonstrate that acclimatization to heat coincides with: (1) a lower number of human chorionic gonadotrophin (hCG) receptors (P less than 0.01) in the Leydig cell, (2) higher affinity of the Leydig cell for hCG (P less than 0.05), (3) lower hCG-stimulated cyclic AMP production (P less than 0.05) by the Leydig cell and (4) lower capacity of the Leydig cell to synthesize testosterone (P less than 0.01) after hCG challenge. It is suggested that the major cellular alteration responsible for the decreased testosterone secretion by the Leydig cell lies distal to the step involving the binding of the trophic hormone to its receptor and that heat-acclimatization induces changes in the integrity of the various cellular membranes leading to the impeded function of adenylate cyclase and 17 beta-hydroxysteroid oxidoreductase.
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PMID:Activity of LH receptor, LH-stimulated cyclic AMP and testosterone production in the Leydig cell of heat-acclimatized rats. 608 1

Decapsulated testes from adult rats were digested with collagenase, and the fraction enriched in germinal and Leydig cells was applied to a 0-4% continuous metrizamide gradient and centrifuged. This leads to separation of a germinal cell fraction and two putative Leydig cell populations that bind human choriogonadotropin, but only one of which responds to the gonadotropin with marked increase in testosterone production. Adenylate cyclase activity was present in these three fractions, and Mn2+ was more effective than Mg2+ as a divalent cation. The adenylate cyclase activity associated with the germinal cell fraction was just marginally stimulated by fluoride and by the non-hydrolyzable GTP analog 5'-guanylimidodiphosphate, while that associated with the Leydig cell populations was stimulated to a greater degree depending upon the type of divalent cation. Only the Leydig cell populations exhibited marked human choriogonadotropin-sensitive stimulation of adenylate cyclase activity in the presence of 5'-guanylimidodiphosphate above that observed with the GTP analog alone. These results suggest the presence of distinct adenylate cyclases in adult rat testis and indicate that both populations of Leydig cells are capable of producing cyclic AMP in response to gonadotropins such as human choriogonadotropin.
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PMID:Demonstration of distinct forms of testicular adenylate cyclases associated with germinal and Leydig cell fractions. 628 12

Cell free desensitization of a tumour Leydig cell plasma membrane adenylate cyclase has been demonstrated in the presence of guanine nucleotides. In experiments in which the membranes were pre-incubated with various nucleotides and LH, it was shown that this decreased adenylate cyclase activity was dependent on the presence of GTP and occurred both in the presence and absence of ATP. While pre-treatment with LH alone appeared to enhance subsequent adenylate cyclase activity, this hormone was able to potentiate the desensitizing effect of GTP. The desensitizing effect of GTP was not inhibited by sodium fluoride. In contrast, the GTP analogue p(NH)ppG (guanosine 5'beta, gamma-imido triphosphate) caused a persistent activation of the adenylate cyclase. GMP and guanosine also initially inhibited the adenylate cyclase activity, but this was entirely reversed by p(NH)ppG plus LH. GDP in addition to GTP caused desensitization but this was only partially reversed by p(NH)ppG plus LH. It is proposed that in similarity with the ovary (Bockaert et al. 1976; Ezra & Salomon 1982a) desensitization of Leydig tumour cell plasma membrane adenylate cyclase may involve a GTP-mediated phosphorylation step.
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PMID:Guanine nucleotide mediated desensitization of adenylate cyclase in cell free preparations from a Leydig cell tumour. 629 16

A rapid and marked amplification of LH and FSH-stimulated cyclic AMP accumulation and steroid secretion is produced by adenosine in luteal and granulosa cells, respectively, of both the rat and the human ovary. The rat Leydig cell response to LH, however, was unaffected by adenosine. In the luteal cell, adenine nucleotides and adenosine were equipotent with decreasing activity shown by inosine, adenine and hypoxanthine--guanosine, guanine, xanthine and pyrimidines were inactive. Both an extracellular and intracellular site appears to be involved in adenosine amplification of LH--the extracellular site accounted for about 20% of the response and may be a catalytic receptor site. The intracellular site was directly related to an increase in luteal cell ATP levels in which adenosine appears to serve as a selective prosubstrate for hormone activated adenylate cyclase. The luteal antigonadotropic action of PGF2 alpha was blocked by adenosine and these modulators were shown to be competitive antagonists of LH-stimulated cyclic AMP accumulation. Due to the ubiquitous nature of both adenosine and PGF2 alpha, (conditions have been described in other systems for their rapid release,) it is suggested that they may serve as important local humoral modulators of gonadotropin action for regulation and control of ovarian function.
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PMID:Purine modulation of LH action in gonadal cells. 631 Feb 56

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


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