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)

The mechanism of stimulation of insulin release from isolated rat islets by 0.3 mM SaRI 59-801 (DL-alpha-dimethylaminomethyl-2-[ 3-ethyl-5-methyl-4-isoxazoyl]-1H-indole-3-methanol) was investigated, considering cAMP concentration and Ca2+ uptake. Ten millimolar theophylline or 1 mM 1-methyl-3-isobutylxanthine, which inhibit cAMP phosphodiesterase, each greatly increased the stimulation of insulin release by 59-801. Forskolin (0.1 mM), an activator of adenylate cyclase, or 1 mM dibutyryl cAMP also potentiated 59-801, suggesting that 59-801 does not elevate islet cAMP but is potentiated by other compounds that do. Measurement of cAMP in islets by radioimmunoassay confirmed that it was not significantly elevated by 59-801 but was increased sevenfold by forskolin or 1-methyl-3-isobutylxanthine. SaRI 59-801 was not effective in the absence of Ca2+ and presence of 1 mM EGTA. Agents that block entry of Ca2+ into beta-cells, verapamil, nifedipine, or CoCl2, inhibited the release of insulin in response to 59-801. Studies of 45Ca2+ uptake by isolated islets revealed an increased uptake in the presence of 59-801 and blockage of this effect by 50 microM verapamil. Thus, the stimulation of insulin secretion by 59-801 appears to involve a stimulation of Ca2+ uptake rather than an increase of cAMP concentration. The mechanism of stimulation of Ca2+ uptake by 59-801 requires further investigation.
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PMID:Stimulation of insulin secretion from isolated rat islets by SaRI 59-801. Relation to cAMP concentration and Ca2+ uptake. 240 49

1. Membrane currents were recorded from voltage-clamped Xenopus oocytes in response to bath application of various divalent cations. 2. In oocytes from 93 of 160 frogs tested, Co2+ ions evoked slow, oscillatory membrane currents. Sensitivity to Co2+ varied greatly between oocytes from different frogs, but was relatively consistent for oocytes taken from the same ovary. Oocytes with high sensitivity had response thresholds of 5-10 microM, and gave currents greater than 1 microA to 1 mM-CoCl2. In contrast, oocytes from some frogs gave no oscillatory response even to 10 mM-CoCl2. With responsive oocytes, Cd2+, Ni2+, Zn2+, Mn2+ and Cr2+ ions (5 microM to 1 mM) also elicited oscillations, whereas Sr2+, Ba2+ and Ca2+ (0.1-10 mM) showed very little activity, and Mg2+ ions, none. 3. Responses to divalent cation were well preserved in defolliculated oocytes, indicating they were generated in the oocyte membrane itself, and were not dependent on the presence of enveloping follicular cells. 4. The oscillatory currents reversed around -20 mV (the chloride equilibrium potential) and rectified strongly at potentials more negative than about -60 mV. The oscillations were mimicked by intraoocyte injection of inositol 1,4,5-trisphosphate (IP3), were largely preserved after removal of external Ca2+, but were abolished following chelation of intracellular Ca2+ by EGTA. Intraoocyte injection of Co2+ ions failed to generate oscillatory currents. 5. Currents elicited by divalent cations resembled the oocyte's oscillatory responses to acetylcholine and a serum protein. However, the response to divalent cations was not blocked by atropine and furthermore, the relative sensitivities to these agonists varied independently between oocytes from different frogs. 6. We conclude that extracellular Cd2+, Ni2+, Zn2+, Co2+, Mn2+ and Cr2+ interact with the oocyte surface to raise cytosolic levels of inositol phosphates. This causes mobilization of intracellular Ca2+, in turn activating Ca2+-gated Cl- channels in the oocyte membrane. 7. In addition to the large oscillatory currents, divalent cations generated small (5-50 nA), smooth, maintained currents associated with decreases in membrane conductance. The size and ionic basis of these currents varied between oocytes from different frogs. 8. Zinc ions also elicited smooth currents, associated with an increase in membrane conductance, and carried predominantly by K+. This response was specific to Zn2+ and occurred independently of oscillatory Cl- currents. The K+ current was abolished by defolliculation, was potentiated by the cyclic AMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine,and showed facilitation with K+ currents generated by the adenylate cyclase activator forskolin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Membrane currents elicited by divalent cations in Xenopus oocytes. 248 82

The stimulation of GH secretion from the anterior pituitary by synthetic GRF (hpGRF) is associated with a rapid increase in cAMP production. Within 5 min of the addition of 1 nM hpGRF to cultured rat anterior pituitary cells, intracellular cAMP levels are elevated 6-fold, with a maximal response being observed at 30 min. cAMP accumulation in the extracellular medium is also enhanced by this peptide. Comparison of the two cellular responses (GH secretion and cAMP formation) at various concentrations of hpGRF indicates that 10 times more hpGRF is required to obtain half-maximal stimulation of cAMP production than for GH secretion. Somatostatin totally blocks hpGRF-stimulated GH release, but only partially attenuates cAMP production in the presence or absence of a phosphodiesterase inhibitor. Verapamil also inhibits GH release in response to hpGRF, but, unlike somatostatin, this effect is not associated with an attenuation of cAMP production. In fact, intracellular cAMP levels are slightly augmented in the presence of verapamil, indicating that Ca2+ is required for hormone release but not for the activation of adenylate cyclase. Consistent with this is the observation that the release of GH due to 8-bromo-cAMP is also blocked by verapamil. A requirement for Ca2+ is further indicated by the inhibitory effects of CoCl2 and CdCl2 on both basal and hpGRF-stimulated GH release. These results suggest that cAMP may play a role as an intracellular mediator of GRF action in somatotrophs and that Ca2+ is required for the release process. Somatostatin may exert its inhibitory effects on GH secretion either by interfering with cAMP production or by an action on the secretory process subsequent to cAMP production.
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PMID:Stimulation of adenosine 3',5'-monophosphate production by growth hormone-releasing factor and its inhibition by somatostatin in anterior pituitary cells in vitro. 619 79

ACTH superfused onto mouse adrenal zona fasciculata tissue caused a transient, dose-dependent membrane depolarization. The log of the dose of ACTH was linearly related to the magnitude of depolarization. The onset of depolarization was rapid and dose dependent. Resting membrane potential changes observed after ACTH were blocked by CoCl2 but not tetrodotoxin or 4-aminopyridine, indicating that these depolarizations were dependent primarily on transmembrane Ca++ flux. CoCl2 also significantly blocked ACTH-stimulated adrenal steroid production; 4-aminopyridine had a much smaller and greatly delayed effect, whereas tetrodotoxin had no detectable effect on steroidogenesis. cAMP administration to adrenal zona fasciculata cells elicited transient, dose-dependent membrane depolarizations, which closely resembled those observed after ACTH treatment. In contrast to ACTH, CoCl2 did not block the cAMP-induced depolarization. These and other studies indicate that ACTH initiates a complex series of events by which steroidogenesis is stimulated. One mechanism may involve a change in membrane permeability to Ca++ independently of cAMP generation; a second mechanism may involve the activation of adenylate cyclase which subsequently influences the membrane conductance of the fasciculata cell membrane.
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PMID:Membrane potential changes of mouse adrenal zona fasciculata cells in response to adrenocorticotropin and adenosine 3',5'-monophosphate. 627 36

Unlike mammals, the goldfish is unique in having dopamine (DA) D1 receptors in the anterior pituitary. In this species, DA stimulates growth hormone (GH) release via D1 receptors coupled to the cAMP-dependent pathway. To further examine the postreceptor mechanisms of this novel pituitary DA D1 system, the role of extracellular Ca2+ ([Ca2+]e] in mediating DA D1-stimulated GH release was studied using dispersed goldfish pituitary cells. The GH responses to DA (1 nM-10 microM), the D1 agonist SKF38393 (1 microM), and the Ca2+ ionophore A23187 (10 microM) were abolished by incubation with Ca(2+)-deficient medium. Incubation with depolarizing doses of KCl (10-25 mM), which activate voltage-sensitive Ca2+ channels (VSCC), induced GH release in a dose-dependent manner. In contrast, the VSCC blockers nifedipine (10 microM), nicardipine (10 microM), and verapamil (10 microM) and the inorganic competitor of Ca2+ entry CoCl2 (5 mM) blocked the GH responses to DA (1 microM) as well as SKF38393 (1 microM). These results strongly indicate that the entry of [Ca2+]e via VSCC is an essential part of the signal transduction mechanisms mediating DA D1-stimulated GH release in the goldfish. In this study, the possible interactions between the Ca(2+)- and cAMP-dependent pathways in DA-induced GH secretion were also investigated. The membrane-permeant cAMP analogue 8Br.cAMP (1 mM) and the adenylate cyclase activator forskolin (10 microM) stimulated GH release from goldfish pituitary cells. These GH responses were suppressed by incubation with Ca(2+)-deficient medium or with the VSCC blocker nifedipine (10 microM). Furthermore, the GH responses to forskolin (10 microM) and the nonselective DA agonist apomorphine (1 microM) were not additive to that of the Ca2+ ionophore A23187 (10 microM). These results suggest that [Ca2+]e entry induced by DA D1 stimulation occur at steps after activation of the cAMP-dependent pathway.
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PMID:Entry of extracellular calcium mediates dopamine D1-stimulated growth hormone release from goldfish pituitary cells. 792 40