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)

In dispersed acinar cells from guinea pig pancreas, cholecystokinin variants (CCK39 and CCK33) or carboxyl-terminal octapeptide of cholecystokinin (CCK-OP) caused significant increases in outflux of 45Ca, cyclic GMP, and release of amylase. In homogenates of acinar cells each peptide caused a significant increase in adenylate cyclase activity. For each function tested (1) CCK39 was equipotent with with CCK33, (2) CCK39 and CCK33 were 10 to 30 times less potent than CCK-OP, (3) the efficacies of CCK39, CCK33, and CCK-OP were the same, and (4) none of these effects were altered by concentrations of atropine sufficient to abolish the action of muscarinic cholinergic agents.
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PMID:Effect of cholecystokinin variant (CCK39) on dispersed acinar cells from guinea pig pancreas. 19 32

A primary culture of human antral somatostatin cells has been developed and used in release studies. The phorbol ester, phorbol 12 myristate 13-acetate, caused a concentration-dependent increase in immunoreactive somatostatin secretion with a 1-mumol/L concentration resulting in a 40-fold stimulation (basal 0.28% +/- 0.7% total cell content vs. 13.8% +/- 2.2% TCC, P less than 0.005). The calcium ionophore, A23187, resulted in a significant stimulation only at 1 mumol/L (basal 0.28% +/- 0.7% TCC vs. 2.2% +/- 0.5% total cell content, P less than 0.05). However, addition of the ionophore at 1 mumol/L with the phorbol ester resulted in a potentiation of the response at all concentrations tested. Removal of extracellular calcium by chelation with EGTA reduced the response to that seen with the phorbol ester alone. Forskolin at 0.1 mmol/L resulted in a five-fold increase (basal 0.6% +/- 0.2% total cell content vs. 2.8% +/- 0.9% total cell content, P less than 0.02) and was 1000-fold less potent than the phorbol ester. The peptides bombesin and gastrin at concentrations up to 1 mumol/L had no effect on basal secretion. Cholecystokinin-8 significantly stimulated somatostatin secretion with a maximal effect at 0.1 mumol/L resulting in an eightfold increase (basal 0.2% +/- 0.04% total cell content vs. 1.5% +/- 0.4% total cell content, P less than 0.02). These results indicate that human antral D cells are more responsive to agents acting through the c-kinase pathway (phorbol 12 myristate 13-acetate, A23187, and cholecystokinin) than adenylate cyclase (forskolin).
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PMID:Release of somatostatin immunoreactivity from human antral D cells in culture. 197 18

Gastrotropin (GT), a protein previously isolated from porcine ileal mucosa, with a molecular mass of 14,054 daltons, was extracted from canine ileum and purified to homogeneity. The canine and porcine peptides had similar relative molecular mass, charge, hydrophobicity, and amino acid compositions. Direct Edman degradation yielded no free amino acids, indicating a blocked NH2-terminus, and a partial sequence determination of the CNBr fragments demonstrated a high degree of homology with porcine GT. Previous studies have indicated that GT is a potent enterooxyntin, and to further characterize these observations we have investigated the actions of both porcine and canine GT on isolated enriched preparations of guinea pig and dog parietal and chief cells. The results of these studies demonstrate that GT is present in more than one species and that the cellular response to porcine and canine GT is identical. The efficacies of canine and porcine GT preparations in stimulating pepsinogen secretion and [14C]aminopyrine uptake were identical and equal to those of cholecystokinin octapeptide (CCK8) and pentagastrin. GT was 100-fold more potent than either of these two major secretagogues. Maximal [14C]aminopyrine accumulation was observed with 10(-8) M GT, with an ED50 of 2 x 10(-9) M compared to pentagastrin, which caused maximal accumulation at 10(-6) M and had an ED50 of 5 x 10(-8) M. Maximal pepsinogen secretion was observed with 10(-7) M GT, with an ED50 of 10(-10) M, compared to 10(-6) M for CCK8, with an ED50 of 10(-8) M. The maximal chief cell response to GT was unaffected by the addition of CCK8 or carbachol, but responded additively with forskolin, indicating that GT uses the same transduction mechanism as CCK8 and carbachol and does not involve the activation of adenylate cyclase. The ED50 values observed with both parietal and chief cells in these studies were close to the basal circulating levels of GT (3.5 x 10(-9) M) in adult pigs. These results clearly demonstrate that GT is a potent component of the enterooxyntin factor identified in studies of the role of the small bowel in the regulation of gastric secretion.
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PMID:Isolation and partial characterization of gastrotropin from canine ileum: further studies of the parietal and chief cell response. 316 34

1. In view of previously demonstrated modulatory effects of CCK8 on DA-sensitive adenylate cyclase activity in the nucleus accumbens, we examined the effects of this neuropeptide in the striatum. 2. Adenylate cyclase activity was measured by conversion of alpha-[32P]ATP into [32P]cAMP. 3. CCK8, when added to the adenylate cyclase assay in concentrations up to 100 microM, failed to significantly alter, either positively or negatively, basal or DA-stimulated (30 or 100 microM) adenylate cyclase activity. Similar results were obtained in the presence of various peptidase inhibitors. 4. Under the assay conditions employed in these experiments, it would appear that there is no effect of CCK8 on DA-sensitive adenylate cyclase in the striatum.
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PMID:Sulfated cholecystokinin octapeptide (CCK8) failed to modulate basal or dopamine-stimulated adenylate cyclase activity in the rat striatum. 338 92

The nucleus accumbens of the rat receives a mixed DA/CCK8 innervation in its posterior part while its anterior part is innervated by distinct DA and CCK8 fibres. In vitro, the addition of CCK8 (0.3-1 microM) potentiated the activating effect of DA (10-30 microM) on adenylate cyclase in tissue homogenates obtained from the posterior part of the nucleus accumbens, whilst this activating effect was reduced by CCK8 in the anterior part. These results suggest the existence of two types of regulation of the D1 receptor by CCK8 depending on the identity (mixed or not mixed) of their innervating fibres.
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PMID:Opposite effects of sulfated cholecystokinin on DA-sensitive adenylate cyclase in two areas of the rat nucleus accumbens. 375 56

Radioligand binding studies of neurotransmitter receptors have provided discrimination at the molecular level, permitting the differentiation of multiple receptor subtypes for several biogenic amines. Using this paradigm we have labeled two distinct receptors each for cholecystokinin (CCK) and for adenosine. Adenosine receptors were labeled in brain with [3H]N6-cyclohexyladenosine (3H-CHA) and [3H]1,3-diethyl-8-phenylxanthine (3H-DP). The adenosine receptor labeled by 3H-CHA appears to be an A1 site, associated with reduction of adenylate cyclase activity, while 3H-DP sites resemble A2 receptors linked to adenylate cyclase enhancement. Cholecystokinin-33 labeled by the Bolton-Hunter procedure with 125I(125I-BH-CCK) labels different receptors in brain and pancreas. The pancreatic receptor does not react with CCK derivatives of fewer than eight amino acids, while the brain receptor does recognize pentagastrin, the carboxyl-terminal five amino acids of CCK. The "brain type" CCK receptor may normally interact with CCK-4, the carboxyl-terminal tetrapeptide of CCK, recently identified as a unique neuropeptide highly concentrated in the brain. CCK-8, the other major molecular form of CCK, may be the endogenous ligand for the "pancreatic type" receptor.
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PMID:Multiple neurotransmitter receptors in the brain: amines, adenosine, and cholecystokinin. 610 42

Peptides of the cholecystokinin family, but mainly the sulphated octapeptide (CCK8), have been found in brain extracts of several species. High amounts are present in axons and nerve endings in the rat neostriatum (caudate-putamen) and a role for cholecystokinin as a neurotransmitter in this functionally important area is possible. We have incubated slices of rat caudate-putamen (CP) to study the release of cholecystokinin-immunoreactivity (CCK-IR) in vitro. The release of CCK-IR was induced by veratridine. It was dependent on the presence of Ca2+ in the incubation medium and was blocked by tetrodotoxin. We now present evidence that dopaminergic agonists added to the slices modulate the veratridine-induced release via different groups of receptors. Receptors which mediate an enhancement of the release of CCK-IR seem to be located on afferent axons and nerve endings and are possibly of the D-2 subtype. Receptors which mediate an attenuation of the release are probably situated on cells intrinsic to the CP. These receptors seem to be coupled to adenylate cyclase and might thus be of the D-1 subtype. There is also evidence that endogenous dopamine when released enhances the secretion of CCK-IR.
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PMID:Dopamine modulates cholecystokinin release in neostriatum. 682 7

1. A possible interaction between cyclic AMP and nitric oxide (NO) in mediating the relaxant effect of vasoactive intestinal polypeptide (VIP) on intestinal smooth muscle cells has been investigated. The effects of the inhibitor of NO synthesis, NG-nitro-L-arginine methyl ester (L-NAME), have been studied on VIP-, forskolin-, and 8 bromo-cyclic AMP- induced relaxation of cells, dispersed by enzymatic digestion of muscle strips from the circular layer of guinea-pig ileum. 2. VIP alone did not modify the length of isolated muscle cells. By contrast, when the cells were contracted by cholecystokinin octapeptide, CCK8 (10 nM), VIP inhibited this contraction, inducing a concentration-dependent relaxation of the cells. Maximal relaxation was induced by 1 microM VIP (EC50 = 408.2 +/- 16.7 pM). 3. N-ethylmaleimide, inhibitors of adenylate cyclase or somatostatin, abolished the relaxing effect of VIP. (R)-p-cAMPs, an antagonist of cyclic AMP on protein kinase A also inhibited the VIP-induced relaxation by 92.1 +/- 6.3%. Inhibitors of nitric oxide synthase (NOS), L-NAME and L-NMMA, partially inhibited VIP-induced relaxation. The effect of L-NAME was reversed by L-arginine but not by D-arginine. 4. (R)-p-cAMPS and L-NAME also inhibited the cell relaxation induced either by forskolin which directly stimulates adenylate cyclase activity or 8-bromo-cyclic AMP, an analogue of cyclic AMP. 5. When cells were incubated for 30 min with dexamethasone 10 microM, a glucocorticoid known to decrease the synthesis of iNOS, the relaxing effect of a maximal concentration of VIP was decreased by 52 +/- 4% and L-NMMA had no further effect on this residual VIP-induced relaxation. Milrinone, a phosphodiesterase type III inhibitor, potentiated the relaxant effect of VIP. 6. These data demonstrate that the intracellular pathway mediating the relaxant effect of VIP in intestinal smooth muscle cells includes the sequential activation of adenylate cyclase, protein kinase A, activation of NOS and finally production of NO and cyclic GMP. NO could in turn regulate the cyclic AMP-dependent pathway of cell relaxation.
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PMID:VIP-induced relaxation of guinea-pig intestinal smooth muscle cells: sequential involvement of cyclic AMP and nitric oxide. 876 68

Stimulation of the brain CCK2 receptor by the C-terminal octapeptide CCK8 of cholecystokinin (CCK) negatively modulates opioid responses. This suggests the existence of physiologically relevant interactions between endogenous CCK and opioid peptides, opening new perspectives particularly in the treatment of pain or drug addiction. CCK2 receptor-deficient mice were used to analyze the incidence of this gene invalidation on opioid system. Compared with wild-type mice, mutants exhibited the following: (1) a hypersensitivity to the locomotor activity induced by inhibitors of enkephalin catabolism or by morphine; (2) a spontaneous hyperalgesia to thermal nociceptive stimulus, which was reversed by previous administration of the NMDA antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], and a large reduction in analgesic effects of endogenous or exogenous opioids; and (3) a more severe withdrawal syndrome after chronic morphine treatment. As expected, stimulation of mu, delta, and D2 receptors on brain tissue of wild-type animals induced a dose-dependent decrease in adenylate cyclase activity, whereas a striking mirror effect was observed in mutants. All of these results suggest that the absence, in knock-out mice, of the negative feedback control on the opioid system, normally performed out by CCK2 receptor stimulation, results in an upregulation of this system. These biochemical and pharmacological results demonstrate the critical role played by CCK2 receptors in opioid-dependent responses.
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PMID:Deletion of CCK2 receptor in mice results in an upregulation of the endogenous opioid system. 1188 May 31