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 distribution and properties of receptors for corticotropin-releasing factor (CRF) were analyzed in the brain of cynomolgus monkeys. Binding of [125I]tyrosine-labeled ovine CRF to frontal cortex and amygdala membrane-rich fractions was saturable, specific, and time- and temperature-dependent, reaching equilibrium in 30 min at 23 degrees C. Scatchard analysis of the binding data indicated one class of high-affinity sites with a Kd of 1 nM and a concentration of 125 fmol/mg (approximately equal to 30% of the receptor number in monkey anterior pituitary membranes). As in the rat pituitary and brain, CRF receptors in monkey cerebral cortex and amygdala were coupled to adenylate cyclase. Autoradiographic analysis of specific CRF binding in brain sections revealed that the receptors were widely distributed in the cerebral cortex and limbic system. Receptor density was highest in the pars tuberalis of the pituitary and throughout the cerebral cortex, specifically in the prefrontal, frontal, orbital, cingulate, insular, and temporal areas, and in the cerebellar cortex. A very high binding density was also present in the hippocampus, mainly in the dentate gyrus, and in the arcuate nucleus and nucleus tuberis lateralis. A high binding density was present in the amygdaloid complex and mamillary bodies, olfactory tubercle, and medial portion of the dorsomedial nucleus of the thalamus. A moderate binding density was found in the nucleus accumbens, claustrum, caudate-putamen, paraventricular and posterior lateral nuclei of the thalamus, inferior colliculus, and dorsal parabrachial nucleus. A low binding density was present in the superior colliculus, locus coeruleus, substantia gelatinosa, preoptic area, septal area, and bed nucleus of the stria terminalis. These data demonstrate that receptors for CRF are present within the primate brain at areas related to the central control of visceral function and behavior, suggesting that brain CRF may serve as a neurotransmitter in the coordination of endocrine and neural mechanisms involved in the response to stress.
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PMID:Distribution of corticotropin-releasing factor receptors in primate brain. 286 91

The characteristics of somatostatin (SRIF) inhibition of calcium influx stimulated by corticotropin releasing factor (CRF), an activator of adenylate cyclase, and K+, a membrane depolarizing agent, in AtT-20 cells were assessed. Changes in cytosolic calcium levels were measured using the fluorescence probe Quin 2. Both CRF and K+ raise cytosolic calcium levels by stimulating calcium influx. SRIF induced an immediate inhibition of CRF and K+-stimulated calcium influx. This effect was concentration-dependent with IC50 values for SRIF's blockade of CRF and K+ stimulation of 64 +/- 13 pM and 100 +/- 15 pM, respectively. The SRIF analogs, SRIF 28, Trp8-SRIF and Tyr11-SRIF had the same rank order of potency to block CRF and K+-induced calcium influx. The inhibitory effects of SRIF on AtT-20 cells were abolished by pertussis toxin pretreatment. SRIF inhibition of both CRF and K+-induced calcium influx desensitized. The desensitization was rapid (T1/2 approximately 2.5 min), dependent on the concentration of SRIF and not due to the degradation of the peptide. The ability of SRIF to block CRF (cyclic AMP-dependent) and K+ (cyclic AMP-independent)-stimulated calcium influx into AtT-20 cells cannot be separated.
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PMID:Somatostatin inhibits cAMP-dependent and cAMP-independent calcium influx in the clonal pituitary tumor cell line AtT-20 through the same receptor population. 289 36

Animals exposed continuously for 14 days to ethanol vapor in an inhalation chamber at sufficient ethanol vapor concentration to maintain blood ethanol levels from 100-250 mg/100 ml exhibited approximately 36% lower corticotropin-releasing factor binding and 24% lower adenylate cyclase activity in anterior (AL) and neurointermediate lobe (NIL) membranes of the pituitary gland compared to controls not treated with ethanol. To determine the effect of chronic ethanol exposure on proopiomelanocortin (POMC) biosynthesis, the levels of POMC mRNA in the AL and NIL were quantified by Northern blot and slot blot techniques. Ethanol treatment for 1, 7, or 14 days produced a time-related decrease in POMC mRNA levels, relative to total RNA levels, in both the AL and NIL. Ethanol treatment caused a greater reduction in NIL POMC mRNA than in AL POMC mRNA. Exposure to ethanol vapors for 14 days decreased immunoreactive beta-endorphin in plasma by approximately 82%. The observed reduction of immunoreactive beta-endorphin in plasma after long term exposure of rats to ethanol may be related to the alcohol-mediated decrease in corticotropin-releasing factor binding and adenylate cyclase activity, which, in turn, leads to decreased intracellular POMC levels through reduced production of POMC mRNA in the AL and NIL of the rat pituitary gland.
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PMID:Ethanol exposure decreases pituitary corticotropin-releasing factor binding, adenylate cyclase activity, proopiomelanocortin biosynthesis, and plasma beta-endorphin levels in the rat. 293 42

The effects of dopamine on proopiomelanocortin (POMC) gene expression were compared in primary cultures of the anterior and intermediate lobes of the rat pituitary. A single-stranded POMC complementary DNA was used to quantitate POMC messenger RNA levels. Treatment with dopamine (1 microM) for 48 h reduced POMC messenger RNA levels in the intermediate lobe by 77%, but had no effect on POMC gene expression in the anterior lobe. Dopamine D2 receptors were implicated in the response, as bromocriptine (100 nM). reproduced the dopamine inhibition. The responses to dopamine and bromocriptine were antagonized by haloperidol (10 microM). The decrease in POMC messenger RNA levels was dose dependent with ED50 values of about 50 and 0.1 nM for dopamine and bromocriptine, respectively. The accumulation of POMC-derived peptides, beta-endorphin and alpha-melanocyte-stimulating hormone, over 2 days was measured by radioimmunoassay and was shown to parallel the changes in POMC synthesis. The dopamine-induced inhibition of intermediate lobe POMC synthesis was unaffected by isoprenalin (5 microM) and corticotropin-releasing factor (10 nM), although these treatments had stimulatory effects when tested alone. Activating adenylate cyclase with forskolin (1 microM) or treatment with 8-bromocyclic adenosine monophosphate (1 mM) doubled POMC messenger RNA levels, and, when tested against these stimuli, bromocriptine still produced a 30% inhibition of POMC gene expression. These observations suggest that D2 receptor induced inhibition of POMC gene expression is not only mediated by a decrease in cyclic adenosine monophosphate levels. When cells were pretreated with pertussis toxin (100 ng/ml), the bromocriptine-induced inhibition was almost completely lost, suggesting that the dopaminergic inhibition is mediated by guanosine triphosphate binding proteins.
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PMID:Dopamine inhibition of proopiomelanocortin gene expression in the intermediate lobe of the pituitary. Interactions with corticotropin-releasing factor and the beta-adrenergic receptors and the adenylate cyclase system. 296 67

Angiotensin II (AII) inhibited anterior pituitary adenylate cyclase. Whereas GTP was necessary to fully express the AII inhibitory effect, Na+ was not required. The magnitude of inhibition (42 +/- 6%) permitted a pharmacological characterization of the AII receptor involved in adenylate cyclase inhibition. Angiotensin I (AI) was less potent than AII, and deletion of aminoacids in the N-terminal position resulted in a progressive reduction of the Ki (peptide concentration producing half-maximal inhibition). The Ki values were 3 +/- 0.9, 10, and 700 nM for AII, angiotensin III (AIII), and des-Asp, des-Arg-AII, respectively. Sarcosine in position 1 [( Sar, Phe]AII) increased the potency of inhibition (Ki = 0.12 +/- 0.12 nM). Different antagonists of the AII receptors appeared to be partial agonists. There was a very close correlation (r = 0.98) between the respective potencies of a series of AII analogs to inhibit adenylate cyclase and the potencies of these analogs to elicit PRL or ACTH release or to bind to AII-binding sites. Dopamine and AII inhibition of anterior pituitary adenylate cyclase were not additive. This suggests that both receptors are on the same cell and likely on lactotrophs. This hypothesis agrees with the observation that vasoactive intestinal peptide stimulation of adenylate cyclase was inhibited by AII, whereas corticotropin-releasing factor stimulation was unaffected. Although dopamine and AII inhibited the same adenylate cyclase, they had opposing effects on PRL release (inhibition and stimulation, respectively). The possible significance of this observation is related to a model implying that PRL release can be elicited through either a Ca+2 or a cAMP pathway.
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PMID:Pharmacological characterization of the angiotensin receptor negatively coupled with adenylate cyclase in rat anterior pituitary gland. 298 69

The stimulation of ACTH release from anterior pituitary cells by corticotropin-releasing factor (CRF) is mediated by specific, high affinity receptors with a Ka of 10(9) M-1 for ovine CRF. The relationship between ACTH secretion and CRF receptor activation was analyzed in normal and adrenalectomized rats by comparison of ACTH release with changes in CRF receptors and adenylate cyclase activity. The marked increase in plasma ACTH levels that occurred after adrenalectomy (from 71 to 478 pg/ml after 4 days) was accompanied by a progressive decrease in pituitary CRF receptor concentration [by 29 +/- 1%, 75 +/- 2%, 77 +/- 6%, and 80 +/- 4% (+/- SE) after 1, 2, 3, and 4 days, respectively]. Most of this decrease was due to receptor down-regulation rather than occupancy by endogenous CRF, since high dose infusions of CRF (300-500 ng/min) for 30 min before pituitary membrane preparation reduced CRF-binding sites by only 40%. The marked reduction in CRF receptors after adrenalectomy was accompanied by comparable decreases in maximal CRF-stimulated adenylate cyclase activity and sensitivity to CRF (ED50, 3.8 +/- 2.8 vs. 58 +/- 3.7 X 10-9 M CRF in control and 2-day-adrenalectomized rats, respectively). Fluoride-stimulated adenylate cyclase activity was unchanged at 24 h, but was decreased by 28 +/- 7% at later times. Such decreases in CRF receptors and adenylate cyclase activity in adrenalectomized rats were prevented by dexamethasone treatment. In cultured anterior pituitary cells from 4-day-adrenalectomized rats, CRF-stimulated cAMP production was decreased by 40%. However, in contrast to the decreases in CRF receptors and cAMP production, there was a 3-fold increase in CRF-stimulated ACTH release, with no change in sensitivity to CRF. The ability of corticotrophs to maintain increased ACTH release, in conjunction with reduced CRF receptors and CRF-stimulated adenylate cyclase, indicates that elevated ACTH secretion can be maintained by occupancy and activation of only a small number of CRF receptors. This finding also suggests that synergistic interactions between CRF and other regulators of ACTH release may contribute to the sustained increase in ACTH secretion that follows adrenalectomy.
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PMID:Regulation of corticotropin-releasing factor (CRF) receptors in the rat pituitary gland: effects of adrenalectomy on CRF receptors and corticotroph responses. 298 94

Specific binding sites for rat corticotropin-releasing factor (rCRF) are present in rat adrenal medulla, ventral prostate, spleen, liver, kidney, and testis and bovine chromaffin cells in culture. Maximal binding of [125I]rCRF occurred within 25 min at 4 C and was saturable. Scatchard analysis of rCRF binding to rat adrenal membranes and bovine chromaffin cells revealed the existence of two classes of binding sites. One class had a relatively higher apparent affinity and lower number of binding sites, whereas the other class had a relatively lower affinity and higher number of binding sites. CRF induced a dose-related increase in rat adrenal membrane adenylate cyclase activity and cAMP levels in bovine chromaffin cells. Nanomolar concentrations of rCRF maximally stimulated adenylate cyclase activity in rat adrenal membranes and maximally increased cAMP levels in bovine chromaffin cells to 86% and 130% above control values, respectively. The demonstration of specific CRF-binding sites in a variety of peripheral tissues and the finding that activation of specific CRF-binding sites in adrenal tissue stimulates the adenylate cyclase-cAMP system suggest that CRF may have an important regulatory role in various peripheral tissues.
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PMID:Corticotropin-releasing factor binding to peripheral tissue and activation of the adenylate cyclase-adenosine 3',5'-monophosphate system. 298 39

Corticotropin-releasing factor (CRF) is the most potent and effective natural stimulant of corticotropin (ACTH) secretion. In a tumor cell line of the mouse anterior pituitary (AtT-20/D16-16) consisting of a homogeneous population of corticotrophs, CRF is known to increase adenylate cyclase and cAMP-dependent protein kinase activities as well as to release ACTH. To determine whether activation of cAMP-dependent protein kinase is essential for CRF to evoke the secretion of ACTH, an inhibitor (PKI) of this kinase was inserted into AtT-20 cells. This was accomplished by first encapsulating PKI into liposomes and then covalently coupling them to protein A for binding to antibodies directed against an AtT-20 cell surface antigen, N-CAM (neural cell adhesion molecule). The binding of the liposomes to the anti-N-CAM antibodies led to the internalization of the PKI into the tumor cells. The PKI treatment greatly attenuated CRF-stimulated ACTH release as well as the secretory response to beta-adrenergic agonists. However, ACTH release in response to caerulein, an agonist of cholecystokinin 8 receptors, was not altered by the PKI treatment. CRF treatment also increased the levels of mRNA for proopiomelanocortin (POMC), the precursor for ACTH in AtT-20 cells. Application of liposomes containing PKI to AtT-20 cells blocked the ability of CRF and 8-bromo-cAMP, but not phorbol ester, to increase POMC mRNA levels. The results revealed an essential role for cAMP in mediating the effect of CRF on ACTH release and POMC gene expression.
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PMID:Corticotropin-releasing factor-induced adrenocorticotropin hormone release and synthesis is blocked by incorporation of the inhibitor of cyclic AMP-dependent protein kinase into anterior pituitary tumor cells by liposomes. 299 99

High-affinity corticotropin-releasing factor (CRF) receptors which mediate the actions of the hypothalamic peptide on adrenocorticotropic hormone (ACTH) release have been identified in the rat anterior pituitary gland. Occupancy of the pituitary receptor by CRF agonists stimulates ACTH release via activation of adenylate cyclase and cyclic adenosine monophosphate dependent protein kinase. In the regulation of ACTH secretion, the effects of CRF on the corticotroph are integrated with the stimulatory actions of cyclic adenosine monophosphate-independent stimuli such as angiotensin II, vasopressin and norepinephrine, and the inhibitory effects of glucocorticoids and somatostatin. In contrast to the major importance of the inhibitory effect of glucocorticoid feedback on ACTH secretion, somatostatin has relatively little effect on CRF-stimulated ACTH release in the normal rat corticotroph. Following adrenalectomy, the progressive elevation of plasma ACTH levels is accompanied by a concomitant decrease in pituitary CRF receptors. The postadrenalectomy loss of CRF receptors, which is prevented by dexamethasone treatment, is caused by a combination of occupancy and processing of the pituitary sites during increased secretion of the hypothalamic peptide. Recently, specific receptors for CRF have been localized in the rat and monkey brain and adrenal medulla, where they are also coupled to adenylate cyclase. Brain CRF receptors are most abundant in the cerebral and cerebellar cortices and in structures related to the limbic system and control of the autonomic nervous system. The actions of CRF on the central and peripheral nervous systems, as well as on the pituitary gland, emphasize the role of CRF as a key hormone in the integrated response to stress.
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PMID:Receptor-mediated actions of corticotropin-releasing factor in pituitary gland and nervous system. 301 95

Rats were treated chronically with atropine (14 days, 20 mg/kg/day, s.c.) and corticotropin-releasing factor (CRF) receptors and CRF-mediated adenylate cyclase activity were measured in discrete brain regions. Chronic atropine treatment produced significant increases in muscarinic cholinergic receptors in the frontoparietal cortex (30% increase) and hippocampus (20% increase). No significant changes in the concentration of [125I]Tyr0-rat CRF binding sites were observed in olfactory bulb, cerebellum, striatum and hippocampus. In contrast, there was a significant and selective increase (35%) in CRF receptors in the frontoparietal cortex of atropine-treated rats. However, no significant corresponding changes in the Vmax or EC50 of CRF-stimulated adenylate cyclase activity accompanied the upregulation of CRF receptors in the cerebral cortex. These results demonstrate that CRF receptors in rat brain are subject to receptor regulation, the upregulation of CRF receptors occurs as a consequence of chronic muscarinic cholinergic receptor blockade, and this interaction between acetylcholine and CRF may be limited to the cerebral cortex.
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PMID:Increased corticotropin-releasing factor receptors in rat cerebral cortex following chronic atropine treatment. 302 62


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