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 influence of cholera toxin (CT), and thus probably of cyclic AMP, on the capacity of parental lymphoid cells to elicit a graft-versus-host reaction (GVHR) was studied. Toxin-treated DBA/1 mice were used as cell donors and untreated DBA/1xC57B1/6 F1 hybrid mice as recipients, and the GVHR reactivity of the transferred cells was estimated by their ability to induce spleen enlargement or stimulation of antibody formation ('allogenic effect') in the recipients. Spleen cells from donors intravenously injected with 1 microgram CT 1-3 days earlier, gave a significantly stronger GVHR than did spleen cells of untreated mice. Choleragenoid, a toxin analog devoid of the toxin's ability to activate plasma membrane adenylate cyclase even though it binds efficiently to cells, had no effect on the GVHR-inducing capacity of the spleen cells. The enhanced GVHR by spleen cells from toxin-treated DBA/1 animals was reduced to the normal level when the donor cells were transferred along with lymphoid cells from untreated animals of the same strain. Spleen was the most powerful source of the suppressive influence. No evidence for a redistribution of suppressor cells following administration of CT was found. Spleen cells from mice syngeneic with the recipients had no suppressive effect. The results suggest that parenterally administered CT, directly or indirectly, can inhibit a cell population in spleen which normally exerts an antigen-specific suppressive regulatory influence on the development of GVHR.
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PMID:Interaction of cholera toxin and toxin derivatives with lymphocytes. III. Modulating effects in vivo by cholera toxin on the graft-versus-host reactivity of lymphoid cells: suggested inhibition of suppressor cells. 2 37

Regulation of P(1)450 gene expression in mouse hepatocytes from responsive (C57BL/6) and non-responsive (DBA/2) strains in primary culture was investigated with respect to aryl hydrocarbon hydroxylase (AHH) activity and P450 transcript levels. Although significant induction of AHH activity in C57BL/6 mouse hepatocytes after exposure to benz[aanthracene (BA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was observed 24 h after the beginning of cultivation, the response was more prominent after longer periods. AHH induction in DBA/2 mouse hepatocytes by TCDD was also evident after 24 h treatment, but that by BA was delayed, only becoming significant after 3 days. Limited treatment with cycloheximide (CHI) for the initial 8 h affected AHH activity measured after 24 h; BA-induced AHH activity was decreased if the treatment started day 1 after seeding of the cells from either strain, whereas if started at day 3 the enzyme activities in hepatocytes from C57BL/6 strain were approximately doubled and those from DBA/2 increased to 130%. Treatment with dibutyryl cAMP or forskolin, a specific activator for adenyl cyclase, increased BA-induced AHH activities. 3-Methoxybenzamide, a specific inhibitor of poly(ADP-ribose) polymerase, significantly increased both basal and BA-induced AHH activities of hepatocytes from both strains at days 3 and 5, reduction of P(1)450 transcripts also being evident in the latter case. The observations indicate qualitatively similar but quantitatively different regulation of AHH induction in both responsive and non-responsive mouse strains. Furthermore the regulation changed with increasing cultivation period. Previously described regulation mechanisms in cultured cells were observed to operate a few days after seeding, possibly after adaptation of hepatocytes to the culture conditions.
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PMID:Regulation of mouse P(1)450 gene expression in monolayer-cultured hepatocytes from responsive and non-responsive strains. 184 69

The immune response of C57BL/6 mice to allogeneic (DBA/2) mastocytoma cell suspensions was profoundly suppressed by intraperitoneal administration of 1 mug cholera enterotoxin 4 days after antigenic stimulation. The immune response assayed 11 days after antigen showed decreased cytolytically active thymusderived (T) lymphocytes and markedly depressed serumagglutinating titers. A comparable suppression of the immune response to skin allografts (DBA/2-->C57BL/6) was also effected by cholera toxin administration, although there was no prolongation of allograft survival. The mechanism of the immune suppression is apparently related to the known adenylate cyclase stimulatory activities of choleragen.
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PMID:In vivo suppression of the immune response to alloantigen by cholera enterotoxin. 435

The effects of morphine on plasma cyclic nucleotide levels and on locomotor activity were investigated in four inbred strains of male mice. Morphine increased both cyclic AMP and cyclic GMP levels as well as locomotor activity in C57BL/6N mice. In BALB/cAnN mice, morphine increased plasma cyclic GMP levels and motor activity without changes in plasma cyclic AMP levels. In C3H/HeN mice, morphine increased plasma cyclic GMP levels without changing cyclic AMP levels and motor activity, but neither plasma cyclic nucleotide levels nor motor activity were increased by morphine in DBA/2N mice. Epinephrine and carbachol increased plasma cyclic AMP and cyclic GMP levels, respectively, in both C57BL and DBA mice. These results show that there is a significant strain difference in the effects of morphine on plasma cyclic nucleotide levels as well as motor activity. The major cause of strain difference in the effects of morphine on cyclic nucleotide levels is unlikely to be due to the difference in the regulation of adenylate cyclase linked to adrenoceptors or that of guanylate cyclase connected with cholinoceptors.
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PMID:Strain difference in morphine-induced increase in plasma cyclic AMP and cyclic GMP levels in relation to locomotor activity in male mice. 628 69

Cyclic adenosine monophosphate (cAMP) is an intracellular second messenger which modulates T cell function. NKH477 is a direct adenylate cyclase activator derived from forskolin and now under clinical investigation as a positive inotropic agent. While the immunosuppressive effects of forskolin on lymphocytes have been reported, little is known about its effects in vivo. In this study, we investigated whether NKH477 has immunosuppressive effects in mice, namely on cardiac allograft survival, and on the generation of cytotoxic T lymphocytes (CTL), T cell proliferation in mixed lymphocyte reaction (MLR), and production of interleukin-2 (IL-2) in MLR and in mitogen response. We assessed the effects of standard immunosuppressant cyclosporin A (CsA) on IL-2 production and on allograft survival to estimate the intensity of rejection in this acute rejection model. Saline-treated C57BL/6 (H-2b) mice rejected DBA/2 (H-2d) cardiac allografts with a median graft survival time of 10 days. In contrast, median graft survival was prolonged to 12 and 15 days in mice treated with NKH477 at 1 and 3 mg/kg/day, respectively (P < 0.01 vs control). The equivalent dose of CsA (40 mg/kg/day) to the maintenance dose after clinical cardiac transplantation prolonged median graft survival time to 15.5 days, indicating that high dose of NKH477 was as efficacious as lower dose of CsA. Addition of NKH477 to the culture medium suppressed the generation of CTL, T cell proliferation in MLR, and production of IL-2 in MLR and in mitogen response. These results suggest that NKH477 exerts a beneficial effect on murine cardiac allograft survival by modulating T cell function.
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PMID:Immunomodulation by an adenylate cyclase activator, NKH477, in vivo and vitro. 861 48

Group III metabotropic glutamate receptors (mGluR4, 6, 7, 8) are negatively coupled to adenylate cyclase and, when activated presynaptically, decrease the release of glutamate and GABA. We have used intracerebroventricular injections of agonists and antagonists believed to act selectively on these receptors to study the pro- or anti-convulsant effects of mGluR III activation in nonepileptic (Swiss-Webster) and epileptic (DBA/2) mice. In both mouse strains the prototypic agonists L-2-amino-4-phosphonobutanoate (LAP4) and L-serine-O-phosphate are proconvulsant. The supposed antagonists (S)-2-methyl-2-amino-4-phosphonobutanoate (MAP4) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG), have a predominantly proconvulsant effect. (S)-alpha-methyl-3-carboxyphenylalanine, which is a potent and selective antagonist for LAP4 in the cortex, is anticonvulsant in DBA/2 mice and decreases the convulsant effect of N-methyl-D-aspartate, 3,5-dihydroxyphenylglycine, LAP4 and MPPG in Swiss-Webster mice. These data suggest that reduced inhibitory transmission may be more significant than reduced synaptic release of glutamate following group III mGluR activation.
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PMID:Convulsant and anticonvulsant actions of agonists and antagonists of group III mGluRs. 885

Transgenic and knockout mice are used extensively to elucidate the molecular mechanisms of hippocampal synaptic plasticity. However, genetic and phenotypic variations between inbred mouse strains that are used to construct genetic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recording methods, we compared the membrane biophysical, cellular electrophysiological, and synaptoplastic properties of hippocampal CA1 neurons in four specific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hippocampal long-term potentiation (LTP) induced by theta-pattern stimulation, and by repeated multi-burst 100-Hz stimulation at various interburst intervals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenance of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was significantly enhanced in129/SvEms slices, but not in DBA and CBA slices. Long-term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons showed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synaptically-evoked glutamatergic postsynaptic currents did not significantly differ among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduced hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitation induced by forskolin (an activator of adenylate cyclase) and IBMX (a phosphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic facilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not in BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic facilitation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some inbred mouse strains may be "tuned" to particular temporal patterns of synaptic activity. From a broader perspective, our data support the notion that strain-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use genetically modified mice to explore the molecular bases of synaptic plasticity.
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PMID:Differential maintenance and frequency-dependent tuning of LTP at hippocampal synapses of specific strains of inbred mice. 1106 91