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)

Vasoactive intestinal polypeptide (VIP)-immunoreactive nerves have been demonstrated in close association with the islets of Langerhans, and VIP has been shown to stimulate insulin and somatostatin secretion. Using [125I]VIP and membranes prepared from rat insulinoma (RIN) cells, i.e., the subclones m5F (m5F; mainly insulin-secreting) and 14B (14B; mainly somatostatin-secreting), it was found that VIP (10(-10)-10(-7) M) competitively inhibited the binding of [125I]VIP. A single class of high affinity binding sites with Kd values of 0.40 +/- 0.06 nM and 0.36 +/- 0.08 nM for m5F and 14B, respectively, with a corresponding number of binding sites (Bmax) of 163 +/- 20 and 254 +/- 51 fmol/mg protein was observed. The rank order of potency in inhibiting [125I]VIP binding was in both cell lines: VIP greater than helodermin greater than pituitary adenylate cyclase activating polypeptide 1-27 (PACAP27) greater than peptide histidine isoleucine (PHI) greater than secretin. VIP caused a dose-dependent increase in cAMP-formation in both m5F and 14B cell membranes with EC50 values of 3.0 and 3.5 nM, respectively, but VIP (1.10(-9)-3.10(-6) M) had no effect on insulin secretion (over 2 h) from the m5F cells. Thus, the data suggest that the VIP-receptors in these neoplastic rat cell lines, despite an apparent coupling to adenylate cyclase activity, seem to be functionally uncoupled to an effect on insulin secretion following an acute exposure to VIP.
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PMID:Demonstration of [125I]VIP binding sites and effects of VIP on cAMP-formation in rat insulinoma (RINm5F and RIN14B) cells. 133 38

A number of regulatory peptides were investigated for their ability to elevate plasma cAMP. Pituitary adenylate cyclase activating peptide (PACAP)-27, PACAP-38, helodermin, helospectin I and II, vasoactive intestinal peptide (VIP), glucagon, parathyroid hormone (PTH), calcitonin and calcitonin gene-related peptide were among the peptides that were highly effective in raising plasma cAMP when given intravenously in equimolar doses to conscious mice. PACAP-27 and -38 were more effective than any of the other peptides. PACAP 16-38, secretin, gastrin-17, galanin, somatostatin, cholecystokinin-8s, pancreatic polypeptide, substance P, peptide YY and neuropeptide Y were inactive and also did not interfere with the PACAP-27-evoked rise in plasma cAMP levels. Repeated injections of PACAP-27 every 30 min caused a progressive reduction in the plasma cAMP response (measured 5 min after each injection). Forskolin, an activator of adenylate cyclase, dose-dependently raised the plasma concentration of cAMP and displayed a synergistic effect when given in a low dose concurrently with PTH or PACAP-38. The phosphodiesterase inhibitor rolipram dose-dependently raised the plasma concentration of cAMP. Combined treatment with PACAP-27 and a threshold dose of rolipram resulted in an exaggerated plasma cAMP response. Kidney hilus ligation suppressed the responses to PACAP-38, PTH, helodermin, helospectin, VIP, glucagon and calcitonin. Hepatectomy suppressed the response to glucagon but was without effect on the response to the other peptides. Pancreatectomy and spleenectomy reduced the response to VIP, but was without effect on the response to the other peptides. PACAP-27 stimulated cAMP efflux from the isolated rat tail vein. Hence, it cannot be excluded that blood vessels contribute to the peptide evoked plasma cAMP response in vivo.
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PMID:Neuropeptides of the vasoactive intestinal peptide/helodermin/pituitary adenylate cyclase activating peptide family elevate plasma cAMP in mice: comparison with a range of other regulatory peptides. 133 41

Somatostatin (SST) receptors activate potassium channels, stimulate protein phosphatases, inhibit adenylate cyclase and close calcium channels. These multiple effects are controlled by guanine nucleotide binding (G) proteins of the pertussis toxin-sensitive Gi and Go types. In the present study we have identified the G proteins coupling with brain SST receptors. To this end, brain SST receptors were solubilized in G-protein coupled form. Binding of the SST analogue MK 678 to the solubilized receptor was completely inhibited by guanosine 5'-O-thiotriphosphate (IC50 = 100 nM), reflecting decreased receptor affinity for agonist following uncoupling of the receptor and G protein(s). Antibodies raised against specific COOH-terminal peptides of the G proteins Gi(1-3), Go, and Gz were used to probe for SST receptor-G protein coupling in this system. Antibodies binding to the COOH-terminal regions of Gi1 and Gi2 (antibody AS) and Gi3 (antibody EC) inhibited binding of 125I-MK 678 (75 pM) by 57 +/- 4% and 48 +/- 5%, respectively. The effects of these antibodies were concentration-dependent and additive, such that in combination AS and EC completely inhibited binding. Antibodies binding to the COOH-terminal region of Go (GO) and Gz (QN) did not affect binding of 125I-MK 678, indicating that neither Go nor Gz are associated with the brain SST receptor. Prelabeling of the receptor with 125I-MK 678 prior to addition of antibody induced the formation of a "locked conformation" of the agonist-bound receptor-G protein complex which was insensitive to antibody. In conclusion, Gi1 and/or Gi2 and Gi3 are coupled in approximately equal proportions to the brain 125I-MK 678-binding SST receptor, accounting for all of the G protein coupling of this receptor.
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PMID:Brain somatostatin receptor-G protein interaction. G alpha C-terminal antibodies demonstrate coupling of the soluble receptor with Gi(1-3) but not with Go. 134 12

We have recently shown that in rat parietal cells the glucagon-like peptide 1 (GLP-1) variants 7-36 amide, 1-37, and 1-36 amide stimulate H+ production as indirectly measured by [14C]aminopyrine (AP) accumulation. This response to the GLP-1 peptides was intracellularly mediated by activation of adenylate cyclase and by adenosine 3',5'-cyclic monophosphate (cAMP) as second messenger. In the present study, we compared prostaglandin (PG)E2, somatostatin, and the protein kinase A antagonist Rp-adenosine-3',5'-monophosphorothioate (Rp-cAMPS) with respect to their inhibitory effects on parietal cell function induced by GLP-1 or histamine. PGE2 and somatostatin noncompetitively inhibited AP accumulation and cAMP production in response to the GLP-1 variants and histamine (IC50): [mean inhibitory concn 5 x 10(-9) M PGE2; 3 x 10(-7) somatostatin]; at their maximal concentrations PGE2 (10(-7) M) and somatostatin (10(-6) M) caused 85 and 65% inhibition, respectively. Treatment with pertussis toxin (PT; 250 ng/ml; 4 h) reversed the inhibitory effect of PGE2 and somatostatin on AP accumulation and cAMP production. At 2 x 10(-3) M (IC50: 3 x 10(-4) M) Rp-cAMPS completely inhibited AP accumulation induced by the GLP-1 variants or histamine; this effect was insensitive to PT. Specificity of Rp-cAMPs as protein kinase A inhibitor is suggested by inhibition of AP accumulation in response to Sp-cAMPS and N6,O2-dibutyryl adenosine 3',5'-cyclic phosphate sodium, and forskolin, activators of protein kinase A and adenylate cyclase, respectively. We conclude that the parietal cell responses to GLP-1 and histamine are inhibited by identical mechanisms. Effects of PGE2 and somatostatin are mediated by the PT-sensitive subunit of adenylate cyclase Gi, whereas Rp-cAMPS interferes with cAMP-dependent mechanisms that are insensitive to PT.
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PMID:Pertussis toxin-sensitive and pertussis toxin-insensitive inhibition of parietal cell response to GLP-1 and histamine. 134 5

The in vivo and in vitro inhibitory effects of a somatostatin (SRIH) analog, octreotide, upon TSH, alpha-subunit, GH, and PRL have been studied, as well as SRIH receptors and their coupling to adenylate cyclase, in nine TSH-secreting pituitary adenomas. From in vivo and cell culture studies, the TSH- and alpha-subunit-secreting adenomas appeared heterogeneous, with four out of the nine tumors cosecreting GH and/or PRL. A single sc injection of octreotide (100 micrograms) lowered plasma concentration of TSH by 40 +/- 5% (mean +/- SE of 5), of alpha-subunit by 27 +/- 9% (n = 5), of GH by 60 +/- 5% (n = 4), and of PRL by 27 +/- 9% (n = 4). In cells cultures, octreotide (10(-8) mol/L) inhibited equally TSH, alpha-subunit, and GH release. 125I-Tyr0-DTrp8-SRIH binding sites were measurable in the nine TSH-secreting adenomas either on membrane preparations (n = 6; Bmax: 152 +/- 73 fmol/mg protein) or on frozen sections by radioautography (n = 3). Their density was variable among TSH adenomas and was lower than that measured in GH-secreting adenomas but higher than in nonfunctioning tumors. Two out of three TSH-secreting adenoma displayed an heterogeneous distribution of 125I-Tyr0-DTrp8-SRIH binding sites. 125I-Tyr0-DTrp8-SRIH specific binding was inhibited by guanosine triphosphate (GTP: 10(-4) mol/L). SRIH inhibited adenylate cyclase in 5/5 TSH-secreting adenomas and a good correlation (r = 0.92, P less than 0.02) was found between 125I-Tyr0-DTrp8-SRIH binding capacity (Bmax) and maximal adenylate cyclase inhibition by SRIH. These results demonstrate in vivo and in vitro inhibition of TSH, alpha-subunit, PRL, and GH secretion by octreotide in TSH-secreting pituitary adenomas. Functional SRIH receptors are present on these tumors and the effect of SRIH on hormonal secretion could be mediated, at least in part, by inhibition of adenylate cyclase. These findings support the medical treatment of this rare type of tumors by SRIH analogs.
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PMID:Somatostatin receptors on thyrotropin-secreting pituitary adenomas: comparison with the inhibitory effects of octreotide upon in vivo and in vitro hormonal secretions. 135 5

Catecholamines acting through beta 1- and beta 2-adrenoceptors cause positive inotropic and chronotropic effects in the human heart. In recent years, however, evidence has accumulated that in the human heart also other receptor systems can affect heart rate and/or contractility. Positive inotropic effects can be mediated by receptor systems acting through accumulation of intracellular cAMP (Gs-protein coupled receptors such as 5-HT4-like, histamine H2, and vasoactive intestinal peptide) or by receptor systems acting independent of cAMP possibly through the phospholipase C/diacylglycerol/inositol-1,4,5-trisphosphate pathway (such as alpha 1-adrenergic, angiotensin II, and endothelin). In the non-failing human heart, however, activation of all these receptor systems induces only submaximal positive inotropic effects when compared with those caused by beta-adrenoceptor stimulation, indicating that in humans the cardiac beta-adrenoceptor-Gs-protein-adenylate cyclase pathway is the most powerful mechanism to increase heart rate and contractility. On the other hand, at least three receptor systems acting through inhibition of cAMP formation (Gi-protein coupled receptors) exist in the human heart: muscarinic M2-, adenosine A1-, and somatostatin-receptors. Activation of M2- and A1-receptors causes negative inotropic effects in the non-failing human heart: in atria activation of both receptors causes decreases in basal as well as in isoprenaline-stimulated force of contraction, but in ventricles only isoprenaline-stimulated force of contraction is depressed.
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PMID:Receptor systems in the non-failing human heart. 135 55

Thyroliberin (TRH), vasoactive intestinal peptide (VIP) and somatostatin (SRIF) act through receptors that are coupled to guanine nucleotide-binding regulatory proteins (G proteins). Regulation of hormone action may occur at the level of G protein coupling to the receptor or effector systems. In this study we demonstrate that prolonged exposure (for up to 48 hr) of cultured rat pituitary adenoma GH3 cells to these hormones caused homologous and to some extent heterologous attenuation of the adenylyl cyclase (AC) (EC 4.6.1.1) responsiveness. In addition, TRH and SRIF diminished both TRH- and guanosine 5'-[beta gamma-imido]-triphosphate-enhanced phospholipase C (PLC) (EC 3.1.4.3) activity within the same time-course. Measurements of cells membrane levels of Gs protein alpha-subunit (Gs alpha), G(i)-1 alpha/G(i)-2 alpha, G(i)-3 alpha, G(o) alpha and G beta by immunoblotting were performed. TRH and VIP upregulated levels of all G proteins except G(o) alpha and G beta. In contrast, SRIF caused a marked reduction of G beta levels. Thus, TRH and VIP, both acting through Gs, both modulated the alpha-subunit levels of this signal transducer, whereas SRIF, which possibly acts through G(i)-2, did not change the steady state level of G(i)-2 alpha. The actions of TRH, VIP and SRIF are multifaceted at the G protein level, where modulations of subtypes not directly involved in their actions may occur. These findings emphasize the complexity expected to be found in the in vivo situation.
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PMID:Hypothalamic hormones modulate G protein levels and second messenger responsiveness in GH3 rat pituitary tumour cells. 135 62

In enzymatically dispersed enriched rat parietal cells we studied the effect of pertussis toxin on prostaglandin E2 (PGE2)- or somatostatin-induced inhibition of H(+)-production. Parietal cells were incubated in parallel in the absence (control cells) and presence of pertussis toxin (250 ng/ml; 4 h). [14C]Aminopyrine accumulation by both pertussis toxin-treated and control cells was used as an indirect measure of H(+)-production after stimulation with either histamine, forskolin or dibutyryl adenosine 3',5'-cyclic monophosphate (dbcAMP) alone and in the presence of PGE2 (10(-9)-10(-7) M) or somatostatin (10(-9)-10(-6) M). PGE2 inhibited histamine- and forskolin-stimulated [14C]aminopyrine accumulation but failed to alter the response to dbcAMP. Somatostatin was less effective and less potent than PGE2 in inhibiting stimulation by histamine or forskolin and reduced the response to dbcAMP. Pertussis toxin completely reversed inhibition by both PGE2 and somatostatin on histamine- and forskolin-stimulated H(+)-production but failed to affect inhibition by somatostatin of the response to dbcAMP. After incubation of crude control cell membranes with [32P]NAD+, pertussis toxin catalysed the incorporation of [32P]adenosine diphosphate (ADP)-ribose into a membrane protein of molecular weight of 41,000, the known molecular weight of the inhibitory subunit of adenylate cyclase (Gi alpha). Pertussis toxin treatment of parietal cells prior to the preparation of crude membranes almost completely prevented subsequent pertussis toxin-catalysed [32P]ADP ribosylation of the 41,000 molecular weight protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pertussis toxin reverses prostaglandin E2- and somatostatin-induced inhibition of rat parietal cell H(+)-production. 135 83

Gastric acid secretion is regulated by an intricate interplay of neural (acetylcholine), hormonal (gastrin), and paracrine (histamine, somatostatin) mechanisms. Receptors for each of these agents and the signal transduction pathways to which these receptors are coupled have been identified on the parietal cell. The stimulatory effect of acetylcholine and gastrin is mediated by an increase in cytosolic calcium, whereas that of histamine is mediated by activation of adenylate cyclase and generation of cAMP. Strong potentiation between histamine and either gastrin or acetylcholine reflects postreceptor interaction between the distinct pathways as well as the ability of acetylcholine and gastrin to release histamine from mucosal ECL cells. The inhibitory effects of somatostatin on acid secretion are mediated by receptors coupled by guanine nucleotide-binding proteins to inhibition of adenylate cyclase activity. All the pathways converge on and modulate the activity of the luminal enzyme, H+K(+)-ATPase, the proton pump of the parietal cell. Precise information on the mechanisms involved in gastric acid secretion has led to the development of potent drugs capable of inhibiting acid secretion. These include competitive antagonists that interact with stimulatory receptors (e.g., histamine H2-receptor antagonists) as well as noncompetitive inhibitors of H+K(+)-ATPase (e.g., omeprazole). The histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, and nizatidine) continue as first-line therapy for peptic ulcer disease and are effective in preventing relapse. Although they are generally well tolerated, histamine H2-receptor antagonists may cause untoward CNS, cardiac, and endocrine effects as well as interference with the absorption, metabolism, and elimination of various drugs. Omeprazole is a weak base that reaches the parietal cell through the bloodstream, diffuses through the cytoplasm, and becomes activated and trapped as a sulfenamide in the acidic canaliculus of the parietal cell. It covalently binds to H+K(+)-ATPase, thereby irreversibly blocking acid secretion in response to all modes of stimulation. The main drawback to its use is its extreme potency, which leads to virtual anacidity, gastrin and ECL cell hyperplasia, hypergastrinemia, and, in rats, to the development of carcinoid tumors.
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PMID:Control of gastric acid secretion. Histamine H2-receptor antagonists and H+K(+)-ATPase inhibitors. 135 65

Somatostatin receptors (SSR) have been identified in membrane homogenates or tissue sections from several hundred human tumors. SSR have been found in most neuroendocrine tumors, ie, growth hormone (GH)- and thyrotropin (TSH)-producing pituitary tumors, endocrine gastroenteropancreatic (GEP) tumors, paragangliomas, pheochromocytomas, medullary thyroid carcinomas (MTC), and small-cell lung carcinomas. SSR have also been found in the majority of malignant lymphomas, in several brain tumors (all meningiomas, most astrocytomas), and in breast tumors. The majority of tumors expressing SSR are rather differentiated, eg, astrocytomas in contrast to glioblastomas, but exceptions such as high-grade malignant lymphomas do exist. An inverse relationship exists between SSR and receptors for epidermal growth factor in lung tumors, glial tumors, and most breast tumors, whereas meningiomas express both receptors simultaneously. A minority of tumors such as ovarian tumors, MTC, and insulinomas express a subtype of SSR characterized by low affinity for the octapeptide SS analogue, octreotide. The function of SSR in human tumors differs according to tumor type; SSR in pituitary and GEP tumors mediate hormone secretion inhibition and possibly have some antiproliferative effects. However, in meningiomas, activation of SSR inhibits forskolin-stimulated adenylate cyclase activity and weakly stimulates proliferation. Although SSR seem to mediate antiproliferative effects in animal models and cell lines of lymphomas and breast and lung tumors, such an effect has not yet been convincingly documented in human primary tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro detection of somatostatin receptors in human tumors. 135 82


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