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)

Fetal exposure to high doses of glucocorticoids, as used to aid lung maturation in the therapy of Respiratory Distress Syndrome, causes growth retardation and interference with development of beta-adrenergic receptor-mediated cell signalling. The current study examined whether lower levels of steroids might instead play a positive trophic role in receptor transduction. Pregnant rats were given dexamethasone at or below the threshold for growth impairment (0.05-0.2 mg/kg) on gestational days 17, 18 and 19, and the beta-receptor-mediated stimulation of adenylate cyclase was evaluated in membrane preparations from heart and kidney. The enzymatic response to isoproterenol was compared with effects on: (1) basal (unstimulated) adenylate cyclase, (2) adenylate cyclase stimulation mediated by forskolin, which bypasses the beta-receptor, and (3) development of beta-receptor binding capabilities, assessed with [125I]pindolol. In the heart, prenatal exposure to dexamethasone produced a dose-dependent enhancement of beta-receptor-mediated stimulation of adenylate cyclase activity; however, both basal and forskolin-stimulated activity were also increased and beta-receptor binding was relatively unaffected. These results suggest that enhanced responsiveness was occurring at the level of the cyclase itself, rather than by effects on receptors on their G-protein coupling to enzyme activity. Promotional effects on adenylate cyclase were detectable at the low dose of dexamethasone, without any evidence of growth impairment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Promotional role for glucocorticoids in the development of intracellular signalling: enhanced cardiac and renal adenylate cyclase reactivity to beta-adrenergic and non-adrenergic stimuli after low-dose fetal dexamethasone exposure. 133 50

Fetal exposure to high doses of glucocorticoids, as used to aid lung maturation in the therapy of Respiratory Distress Syndrome, causes growth retardation and interference with development of beta-adrenergic receptor-mediated cell signalling. The current study examined whether lower levels of steroids might instead play a positive trophic role in receptor transduction. Pregnant rats were given dexamethasone at or below the threshold for growth impairment (0.05-0.2 mg/kg) on gestational days 17, 18 and 19, and the beta-receptor-mediated stimulation of adenylate cyclase activity was evaluated in membrane preparations from heart and kidney. The enzymatic response to isoproterenol was compared with effects on: (1) basal (unstimulated) adenylate cyclase, (2) adenylate cyclase stimulation mediated by forskolin, which bypasses the beta-receptor, and (3) development of beta-receptor binding capabilities, assessed with [125I]pindolol. In the heart, prenatal exposure to dexamethasone produced a dose-dependent enhancement of beta-receptor-mediated stimulation of adenylate cyclase activity; however, both basal and forskolin-stimulated activity were also increased and beta-receptor binding was relatively unaffected. These results suggest that enhanced responsiveness was occurring at the level of the cyclase itself, rather than by effects on receptors or their G-protein coupling to enzyme activity. Promotional effects on adenylate cyclase were detectable at the low dose of dexamethasone, without any evidence of growth impairment. Furthermore, the effects displayed selectivity for age and tissue: adults treated with dexamethasone did not show the effect, and the heart was more sensitively affected than was the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Promotional role for glucocorticoids in the development of intracellular signalling: enhanced cardiac and renal adenylate cyclase reactivity to beta-adrenergic and non-adrenergic stimuli after low-dose fetal dexamethasone exposure. 166 97

Apomorphine (APO), 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127) and 2-di-n-propylamino-5,8-dimethoxytetralin (JMC-181) were examined on a variety of biochemical and pharmacological assays to determine their possible interaction with dopamine (DA) receptors. Nanomolar concentrations of all three compounds displaced [3H]APO from specific high-affinity binding sites in rat striatal membrane preparations, while higher concentrations were required to displace [3H]spiperone or [3H]rauwolscine. APO caused a concentration-dependent increase in the ability to stimulate postsynaptic DA receptors associated with adenylate cyclase (D1-sites) in the carp retina, whereas RDS-127 or JMC-181 were inactive in concentrations up to 300 microM. APO was very active in causing contralateral turning behavior in rats with a 6-hydroxydopamine lesioned substantia nigra (SN); RDS-127 was approximately 8 times less potent in producing contralateral rotations and JMC-181 was inactive. RDS-127 produced biphasic, dose-related changes in rat spontaneous locomotor activity similar to that reported for APO. The locomotor stimulant effects of RDS-127 were 3 times more potent and 4 times greater in duration than that induced by APO. JMC-181 produced primarily sedation in the doses tested. APO, RDS-127 and JMC-181 were active in inhibiting the accumulation of dopa in the caudate nucleus and olfactory tubercle using the in vivo gamma-butyrolactone procedure; 5-hydroxytryptophan accumulations were not altered significantly. RDS-127 was 7 times more potent than APO in inhibiting dopa accumulation in the caudate nucleus and equipotent to APO in the olfactory tubercle. Dopa accumulation was weakly inhibited by JMC-181. When single unit extracellular action potentials were recorded from purported DA-containing neurons in the SN, RDS-127 decreased the firing of neurons in the pars compacta of SN (ID100 = 40 +/- 10 nmol/kg i.v.). In contrast, firing of units in the pars reticulata of SN were not altered or increased in response to RDS-127. The biochemical electrophysiological and behavioral effects of RDS-127 were blocked or reversed by DA receptor antagonists. These data indicate that RDS-127 is significantly more selective than APO in preferentially activating DA autoreceptors as opposed to the postsynaptic DA receptors in the nigrostriatal pathway. The possibilities of designing potent, long acting, nonergot, noncatechol-containing DA receptor agonists are discussed.
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PMID:RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane): central effects of a new dopamine receptor agonist. 640 34