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)

Rat GH-releasing hormone (GHRH), mainly contained in hypothalamic neurons, has also been identified in several extraneural tissues, including the gastrointestinal tract, placenta, ovary, and testis. In the testis, GHRH mRNA is ontogenically regulated, and GHRH immunoreactivity can be observed in interstitial cells and tubules, suggesting an intratesticular role for the peptide. Leydig cells in culture are able to produce hypothalamic releasing hormones, i.e. CRH, which acts as an autocrine negative regulator of Leydig cell function. In this study we investigated whether GHRH is present in Leydig cells and evaluated the role of the peptide in Leydig cell function. Adult Leydig cells in culture produced considerable amounts of immunoreactive GHRH [23.9 +/- 2.1 (+/- SE) pg/10(6) cells.30 min], and the release of the peptide was acutely stimulated by hCG. HPLC analysis of GHRH in media from basal and hCG-treated cultures showed the presence of a single peak eluting at the same retention time as that of hypothalamic rat GHRH. Radioligand binding and activation studies revealed a common receptor for vasoactive intestinal peptide (VIP) and rat GHRH in Leydig cell membrane. Specific binding of [125I]VIP to Leydig cell membranes showed the presence of a single site, with high affinity and low binding capacity. The relative potencies of VIP-related peptides for inhibition of radioligand binding were: VIP > rat GHRH > secretin > human GHRH. In cultured Leydig cells, GHRH and VIP stimulated cAMP production, consistent with coupling of the receptor to the adenylate cyclase system. VIP displayed a lower ED50 than GHRH in stimulating cAMP production (P < 0.01), comparable with the higher binding potency of this peptide. No additive effects of VIP- and GHRH-stimulated cAMP generation were observed, suggesting that both peptides compete for the same receptor protein. GHRH and VIP had no effect on basal steroidogenesis, indicating a lack of tonic actions and compartmentalization of the peptides' effect. On the other hand, GHRH acted as a potentiator of the acute gonadotropin stimulation of testosterone production and cAMP generation. [125I]hCG binding to the Leydig cells in culture showed that GHRH was unable to affect the number or affinity of binding sites for hCG, indicating that the GHRH-sensitizing effect on LH action is beyond the level of gonadotropin binding and possibly is through the facilitation of LH receptor coupling functions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Growth hormone-releasing hormone is produced by rat Leydig cell in culture and acts as a positive regulator of Leydig cell function. 133 49

It has been shown that chronic cold exposure results in selective CRH receptor up-regulation in the intermediate pituitary. Since the intermediate pituitary is under dopaminergic control, the participation of a dopaminergic mechanism in the effect of cold stress was studied in rats treated with dopaminergic agonists and antagonists. CRH receptors were measured by the binding of radioiodinated Tyr-ovine (o) CRH to neurointermediate pituitary membranes of slide-mounted sections. Cold exposure for 60 h caused the expected increase in CRH binding in neurointermediate lobe membranes. Administration of the dopaminergic agonist bromocriptine did not prevent the effect of cold stress, but increased CRH binding in control rats. The dopaminergic antagonist metoclopramide decreased intermediate pituitary CRH binding in control and cold-exposed rats. Bromocriptine administration for 1-8 days caused a progressive increase in the binding of [125I]Tyr-oCRH in neurointermediate pituitary membranes, despite atrophy of the intermediate zone. Scatchard analysis of the binding data indicated that the changes were due to variations in receptor concentration, without changes in affinity. No changes in anterior pituitary CRH receptors were observed with agonist or antagonist treatment. Autoradiographic analysis of CRH binding after 3 days of treatment with bromocriptine or haloperidol confirmed the results observed in membranes and demonstrated that changes in binding were confined to the intermediate lobe. The functional consequences of the changes in CRH binding were studied by analysis of adenylate cyclase activity in cells and homogenates of intermediate pituitaries of rats treated with bromocriptine. In 18-h cultured intermediate pituitary cells from rats treated with bromocriptine for 3 days, CRH-stimulated cAMP production, measured in the presence of phosphodiesterase inhibitors, was increased to levels only slightly higher than those in cells from control rats. Likewise, CRH-stimulated adenylate cyclase, measured by conversion of [32P]ATP to [32P] cAMP, was not significantly different in homogenates from microdissected intermediate lobes from control and bromocriptine-treated rats. The lack of parallel changes in adenylate cyclase responsiveness suggests only partial receptor coupling, probably reflecting an inhibitory effect of dopamine on components of the adenylate cyclase. This study demonstrates that in contrast to the recognized inhibitory effect on cell division and POMC mRNA expression, dopamine causes up-regulation of CRH receptors in the intermediate pituitary. The qualitatively similar and nonadditive effects of cold stress and dopaminergic agonists suggest that a dopaminergic mechanism may be involved in intermediate pituitary CRH receptor regulation during chronic cold stress.
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PMID:Regulation of intermediate pituitary corticotropin-releasing hormone receptors by dopamine. 134 42

Cyclic adenosine monophosphate (cAMP)-mediated signal transduction was evaluated in synaptosomes prepared from rat brain cortex. Adenylate cyclase was responsive to known adenylate cyclase stimulators including peptides (CRH and VIP), catecholamines (norepinephrine and isoproterenol) and ligands that directly stimulate adenylate cyclase (forskolin). Cyclic AMP accumulation also increased approximately 2 to 3-fold, but none of the agonists was able significantly to activate cyclic AMP-dependent protein kinase (A-kinase) in cortical synaptosomes. However, in parallel studies with slices prepared from rat brain cortex, adenylate cyclase activity, cAMP accumulation and A-kinase activity were all stimulated by CRH, VIP, norepinephrine, isoproterenol and forskolin. These data suggest that, in intact synaptosomes, either the cellular machinery which facilitates binding of cAMP to the regulatory subunit of A-kinase is missing or the cAMP produced by adenylate cyclase is not accessible to A-kinase.
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PMID:Evidence that metabolically active synaptosomes lack functional cyclic AMP-dependent protein kinase. 176 Feb 53

The effects of CRH and somatostatin (SRIH) on adenylate cyclase (AC) activity, intracellular free calcium concentrations [( Ca2+]i) and in vitro ACTH release were investigated in six human ACTH-secreting pituitary adenomas. In all tumors, CRH induced a marked stimulation (from 69-210% at 10 nM), whereas SRIH caused a definite inhibition (from 29-50% at 100 nM) of membrane AC. When added together, CRH and SRIH caused a purely additive effect on AC. In adenomatous corticotrophs CRH (10 nM) caused [Ca2+]i to rise from 160 +/- 30 nM (mean +/- SD) to 410 +/- 95 nM. CRH-induced transients were biphasic, with an initial peak predominantly due to redistribution from intracellular Ca2+ stores and a secondary phase due to Ca2+ influx. The effects of CRH on [Ca2+]i were totally independent of the stimulation of AC. In fact, cAMP-elevating agents other than CRH did not modify [Ca2+]i. SRIH (100 nM) decreased resting [Ca2+]i (approximately 20-40%) as well as [Ca2+]i rises induced by CRH, arginine vasopressin, or high K+. The effect of SRIH on [Ca2+]i was maintained in presence of high cAMP levels, while was totally abolished after pertussis toxin pretreatment. CRH (10 nM) stimulated ACTH release (from 22.5 +/- 3.5 to 45.0 +/- 8.5 pmol/L) by an extent similar to that elicited by calcium ionophore and forskolin. By contrast, SRIH (0.1 microM) inhibited both basal and CRH-stimulated ACTH release. In conclusion, in human adenomatous corticotrophs SRIH exerts an inhibitory action by reducing both AC activity and, independently, [Ca2+]i. In this way, SRIH can efficiently counteract the stimulatory action of CRH that in these cells involves activation of both cAMP and Ca2+ pathways.
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PMID:Inhibition of basal and corticotropin-releasing hormone-stimulated adenylate cyclase activity and cytosolic Ca2+ levels by somatostatin in human corticotropin-secreting pituitary adenomas. 197 Aug 28

The factors controlling the expression of the hypothalamic neuropeptide, corticotropin releasing hormone (CRH), are poorly understood. We have used a mouse anterior pituitary cell line, AtT-20, permanently transfected with the human CRH gene as a model for studying the regulation of the CRH gene by cyclic AMP. Previously, we demonstrated that in this system the CRH gene is correctly expressed and appropriately negatively regulated by glucocorticoids. Treatment of five CRH-producing cell lines with an activator of adenylate cyclase (forskolin, 0.1-50 microM for 24 h) caused a dose-dependent and specific increase in the amount of CRH mRNA and radioimmunoassay-detectable CRH peptide secreted into the medium. Ribonuclease protection analysis revealed that the CRH gene was transcribed from multiple transcriptional initiation sites located over several hundred nucleotides. Forskolin treatment resulted in a specific increase in the CRH mRNA transcripts initiating from one of these many transcriptional start sites.
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PMID:Regulated expression of the human corticotropin releasing hormone gene by cyclic AMP. 216 64

The effects of ketoconazole (KC) on secretion and biosynthesis of ACTH in rat anterior pituitary cells were investigated in vitro. KC inhibits the corticotropin releasing hormone (CRH) stimulated ACTH release from rat anterior pituitary fragments in a dose dependent fashion between 1.5 and 100 microM. The effect of CRH to release ACTH was fully restored after KC was removed from the medium. Similar effects were observed in primary cultures of rat anterior pituitary cells: KC decreased dose dependently the basal and CRH stimulated ACTH release. In addition, basal and CRH-stimulated mRNA coding for the ACTH precursor was reduced after preincubation with CK. The effects of KC on ACTH release and biosynthesis seems to be mediated by cyclic AMP (cAMP) since KC inhibits basal and CRH stimulated cAMP release and content within the same dose range. Since the stimulatory effect of cholera toxin, sodium fluoride and forskolin were dose dependently inhibited by KC and since the addition of dibutyryl cAMP abolished the inhibiting effect of KC, it is concluded that KC acts by inhibition of the catalytic component of the adenylate cyclase holoenzyme.
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PMID:Pharmacological modulation of CRH-stimulated ACTH secretion by ketoconazole. 245 Aug 25

The molecular mechanisms involved in the regulation of expression of the rat CRH gene have been examined in rat pheochromocytoma (PC-12) cells transiently transfected with a chimeric gene containing 1.4 kilobases of rat CRH 5'-flanking DNA fused to the bacterial reporter gene encoding chloramphenicol acetyltransferase. Cyclic AMP analogs and activators of adenylate cyclase positively regulate the expression of this chimeric gene in PC-12 cells, inducing chloramphenicol acetyltransferase activity more than 15-fold. The DNA sequence required for this response to cAMP has been localized to a 59 base pair region located between 238 and 180 base pairs 5' to the putative CRH mRNA cap site. This sequence can confer cAMP-responsiveness on a heterologous promoter in an orientation independent fashion and has homology to cAMP regulatory regions from a number of other eukaryotic genes.
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PMID:Identification of a cyclic adenosine monophosphate-responsive element in the rat corticotropin-releasing hormone gene. 285 Nov 1

Over the past twenty years, each of the five major hypothalamic releasing or release-inhibiting hormones has been sequenced and its gene structure determined. With the use of molecular biological techniques, such as in situ hybridization, Northern blot analysis or gene constructs for in vitro or in vivo transfection studies--together with 'traditional' neuroendocrinological techniques, such as immunocytochemistry, radio-immunoassay and portal vessel cannulation--investigators have been able to address major issues in neuroendocrine regulation. Several common themes have emerged: messenger RNA expression is uniformly present in neurons that are immunopositive for the specific hypothalamic hormone. Steady state RNA levels within the hypophysiotropic neuron groups are either increased or reduced by changes in specific target hormones that conform to predictions based on previous physiological data. Regulation by the requisite peripheral hormone is exquisitely anatomically specific and is not evident in extrahypophysiotropic regions. Determining the receptor or genetic basis of this specificity is a major focus of current research. Clarifying the apparently lesser role of afferent neural pathways to the hypothalamus in regulating releasing hormone mRNA levels is also an important challenge. Clinically, the measurement of levels of releasing hormones in the peripheral circulation appears to be of limited usefulness, except in rare cases of ectopic GRH or CRH secretion. For diagnostic purposes, each of the releasing hormones has specific utility in amplifying the release and measurement of pituitary hormones, both to clarify the overall physiological activity of the hypothalamic-pituitary-target hormone axis and to further define the anatomic locus of any underlying disturbance. The usefulness of somatostatin as a diagnostic tool is presently limited, but the development of SS receptor antagonists might have significant impact in future clinical investigation. The molecular mechanisms of action of the hypothalamic hormones have been separated into those whose receptor-effector function is mediated by the cAMP-adenylate cyclase pathway(s), GRH and CRH, and those working through the phosphoinositide-protein kinase C cascade, GnRH and TRH. Each of the hormone receptors is coupled to intermediary G proteins, somatostatin uniquely to the inhibitory subclass. The mechanisms responsible for sensitization (priming) or desensitization are not fully understood but are presumably related to receptor down regulation and protein phosphorylation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular biology and regulation of the hypothalamic hormones. 290 17

Receptors for CRH were identified in the pituitary gland of several primate species, and their binding characteristics were compared to the ability of CRH to elicit ACTH and cAMP responses in vitro. Autoradiographic analysis of the binding of [125I]Tyr-ovine CRH to frozen pituitary sections revealed CRH receptors in the intermediate and anterior lobes of human, marmoset, and cynomolgus monkey pituitaries. In the cynomolgus monkey, a high density of CRH receptors was present throughout the anterior and intermediate lobes. In the human pituitary, binding was concentrated in the anteromedial portion of the gland, whereas in the marmoset, binding was dense in the intermediate lobe and scattered as clusters throughout the anterior lobe. In membrane-rich fractions from the cynomolgus pituitary binding of [125I]Tyr-ovine CRH was time and temperature dependent, and was specific for CRH-related peptides; specific binding was increased by divalent cations and inhibited by guanyl nucleotides. Scatchard analyses of the binding data revealed a single class of high affinity sites [Kd, 1.93 +/- 0.23 (+/- SEM) nM], with a receptor concentration of 605 +/- 121 fmol/mg. In marmoset pituitary membranes, there were fewer receptors (200 +/- 15 fmol/mg), in agreement with the lower autoradiographic density of CRH binding. In anterior pituitary cell cultures from cynomolgus monkeys, CRH caused a dose-dependent stimulation of cAMP production and ACTH release, with half-maximum effective concentrations in the range of the CRH receptor affinity. Vasopressin and norepinephrine stimulated ACTH release to a much lesser extent, but both potentiated the stimulatory effect of CRH. Angiotensin II had no effect alone, but it also potentiated the effect of CRH. These data demonstrate the presence of CRH receptors in the primate pituitary, with characteristics similar to those in other species in their binding properties, coupling to adenylate cyclase, and functional interactions with other regulators of ACTH secretion that mediate the stimulatory effect of the peptide in the corticotroph.
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PMID:Receptors and actions of corticotropin-releasing hormone in the primate pituitary gland. 303 Nov 17

We have investigated the effects of the novel phospholipid drug glyceryl-phosphoryl-O-serine (GPS) on pituitary ACTH and hypothalamic corticotropin releasing hormone secretion in vitro in cultures from both 2- and 24 month-old Sprague-Dawley rats. Basal levels of ACTH in primary cultures of pituitary cells from 24 month-old rats were lower than (100 +/- 12 pg/10(5) cells) in 2 month-old rats (207 +/- 18 pg/10(5) cells). Basal medium corticotropin releasing hormone levels in hypothalamic cultures were higher in 24 month-old rats (45 +/- 7 pg/well/20 min.), than in 2 month-old rats (29 +/- 5.5 pg/well/20 min). Treatment of both pituitary cells with corticotropin releasing hormone and hypothalami with serotonin resulted respectively in a significant, concentration-dependent, increase of medium ACTH and corticotropin releasing hormone. However, concentration-response curves for ACTH and corticotropin releasing hormone were shifted to the right in cultures from 24 month-old rats. Incubation with graded concentrations of GPS produced significant increase in medium ACTH and corticotropin releasing hormone in cultures from 24 month-old rats, whereas the drug was ineffective in stimulating secretion of both hormones from 2 month-old rat cells. In addition, the adenylate cyclase stimulator forskolin and the protein kinase C activator oleyl-acyl-glycerol stimulated ACTH secretion in pituicytes from rats of both ages. However, response to oleyl-acyl-glycerol was blunted in pituicytes from 24 month-old rats. Combination of either forskolin or oleyl-acyl-glycerol with GPS resulted in a potentiation of the effect. Our data confirm an impairment of both pituitary ACTH and hypothalamic corticotropin releasing hormone secretion in the aging rat.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The phospholipid drug glyceryl-phosphoryl-O-serine modulates pituitary adrenocorticotropin and hypothalamic corticotropin releasing hormone in vitro secretion in the aging rat. 775 60


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