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)

Increased myocardial tissue cyclic AMP has been associated with both a positive inotropic and a proarrhythmic effect. We wished to determine whether two agents that increase myocardial cyclic AMP levels by different mechanisms would induce comparable changes in vulnerability of the heart to ventricular fibrillation (VF) and in the inotropic status. Using an isolated perfused rat heart model, we studied the effects of beta-adrenoceptor stimulation by isoproterenol (ISO) and direct activation of adenylate cyclase by forskolin. The ventricular fibrillation threshold (VFT) was taken as an index of the vulnerability to VF and peak left ventricular systolic pressure (LVSP) as a measure of the force of LV contraction. ISO resulted in a dose-related increase in tissue cyclic AMP with a corresponding decrease in VFT and a marked increase in LVSP. Forskolin produced a delayed but exponential increase in cyclic AMP at concentrations greater than 3 x 10(-7) M with relatively small increases in LVSP. With forskolin, the VFT decreased only at extremely high cyclic AMP levels, suggesting that the drug had increased cyclic AMP in a compartmentalized manner. The discrepant effects of ISO and forskolin on VFT could not be explained by changes in heart rate (HR). These results show that an increase in tissue cyclic AMP can have markedly different arrhythmogenic effects depending on the mechanism by which cyclic AMP is increased.
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PMID:Contrasting effects of cyclic AMP increase caused by beta-adrenergic stimulation or by adenylate cyclase activation on ventricular fibrillation threshold of isolated rat heart. 128 Jul 16

[Met5]-Enkephalin (ME) secretion and the expression of proenkephalin A (proENK) mRNA were studied following long-term exposure of bovine adrenal medullary chromaffin (BAMC) cells to pertussis toxin. Treatment with pertussis toxin for 24 h increased the secretion of ME in a concentration- and time-dependent manner. The magnitude of ME secretion continued to increase with time in the presence of pertussis toxin. The intracellular concentration of ME in the pertussis toxin-treated group was not significantly different from controls, suggesting that elevated levels of ME secretion result from increased biosynthesis of ME rather than from release of stored ME. Prolonged (24 h) stimulation of BAMC cells with pertussis toxin also increased proENK gene expression. Pretreatment with nimodipine (a calcium channel blocker) and calmidazolium (a calmodulin antagonist) inhibited both the secretion of ME and the increase in proENK mRNA levels induced by pertussis toxin, while the intracellular calcium antagonist dantrolene and the protein kinase C inhibitors sphingosine and H7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine] were ineffective in blocking pertussis toxin-induced responses. Forskolin (an adenyl cyclase activator) and isobutyl methyl xanthine (a phosphodiesterase inhibitor) increased both ME secretion and proENK mRNA levels; pertussis toxin synergistically increased the secretion of ME with these cyclic AMP-elevating agents but had only an additive effect with these agents on the level of proENK mRNA. Our results suggest that a pertussis toxin-sensitive G protein may tonically regulate the secretion of ME as well as the level of proENK mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pertussis toxin stimulates the secretion of [Met5]-enkephalin and the expression of proenkephalin A mRNA in bovine adrenal medullary chromaffin cells. 128 24

The effect of the domestic Forskolin on lowering the intraocular pressure (IOP) of rabbits was studied. The results showed that the Forskolin significantly lowered the normal IOP of rabbits and blocked the ocular hypertension induced by water load in rabbits (p < 0.01). The maximum decrease value of 2%, 1% and 0.5% of the Forskolin was 0.59. 0.36 and 0.19 kPa (1 kPa = 7.5 mmHg), which showed the noticeable dose-effect relationship. Topical ocular application of Forskolin lowered IOP in 1/2 hour, reached to a peak in 2-3 hours and remained significantly for 10 hours. The pupillary diameter did not change when IOP were reduced. Furthermore, the Forskolin had potent stimulative properties to adenylate cyclase (AC). The greater the ability of the Forskolin to stimulate AC, the stronger the effect of IOP lowering.
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PMID:[The experimental studies of the effect of Forskolin on the lowering of intraocular pressure]. 130 93

The cellular mechanisms underlying beta-adrenergic potentiation in the CA1 region of the rat hippocampus were examined. A 10 min treatment with isoproterenol (ISO) induced a long-term depolarization of the pyramidal neurons that persisted for at least 30 min of washout; the ISO-induced decrease in the calcium-activated potassium conductance (afterhyperpolarization, or AHP) was similarly prolonged. The long-term excitability changes induced by ISO did not depend upon the calcium concentration of the medium and could be elicited in medium containing as little as 240 microM calcium. The persistent increase in population spike induced by ISO was mimicked by superfusion with several cAMP analogs and by forskolin (which directly activates adenylate cyclase), but not by the inactive dideoxyforskolin. Forskolin and cAMP analogs also induced decreases in AHPs that could be quite prolonged, but did not depolarize pyramidal neurons as consistently as did ISO. We hypothesize that activation of beta-adrenergic receptors in the CA1 region of hippocampus may induce an alteration of the hippocampal "state" that can persist for as long as several hours, during which the induction of other forms of plasticity may be enhanced.
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PMID:Long-term increases in excitability in the CA1 region of rat hippocampus induced by beta-adrenergic stimulation: possible mediation by cAMP. 131 Oct 33

Forskolin has long been used to demonstrate the involvement of cAMP in the regulation of cellular function, by virtue of its ability to stimulate adenylate cyclase directly. Recently, however, forskolin has been shown to affect plasma membrane transporter and channel function in a manner unrelated to cAMP. The present study examines whether forskolin-mediated inhibition of a mitochondrial membrane-associated enzyme, 25-hydroxyvitamin D3-24-hydroxylase (24-hydroxylase), also occurs by a cAMP-independent mechanism. Both forskolin and PTH stimulated cAMP accumulation and inhibited 24-hydroxylase activity in a dose-dependent manner in fresh mouse renal tubules. However, the level of inhibition of 24-hydroxylase achieved with forskolin was consistently greater than that obtained with PTH, at comparable levels of cAMP. 1',9'-Dideoxyforskolin, a cyclase-inactive analog of forskolin, also inhibited 24-hydroxylase activity, without stimulating cAMP production. Moreover, both forskolin and 1',9'-dideoxyforskolin directly inhibited 24-hydroxylase in isolated renal mitochondria. Kinetic analysis revealed a competitive mode of inhibition for both agents; however, 1',9'-dideoxyforskolin proved to be a more potent inhibitor of 24-hydroxylase than forskolin (inhibitory constant, 0.25 vs. 22 microM, respectively). Finally, both forskolin and 1',9'-dideoxyforskolin also inhibited inducible 24-hydroxylase in renal tubules prepared from 1,25-(OH)2D3-treated mice. However, inducible 24-hydroxylase activity was less susceptible to inhibition by the diterpenes than the basal enzyme activity. The present study provides evidence for cAMP-independent inhibition of 24-hydroxylase by forskolin and represents the first demonstration of a cAMP-independent effect of forskolin on a protein that is not a plasma membrane-associated transporter or channel. Our data advocate caution in the interpretation of studies using forskolin to assess the role of cAMP in cellular processes.
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PMID:Inhibition of 25-hydroxyvitamin D3-24-hydroxylase by forskolin: evidence for a 3',5'-cyclic adenosine monophosphate-independent mechanism. 131 47

The colonic epithelial cell line T84 has been shown to be a good model to investigate the regulation of Cl- secretion by the adenosine 3',5'-cyclic monophosphate (cAMP)-mediated second messenger cascade. Regulated exocytic insertion and endocytic retrieval of transport proteins, or proteins that regulate transport proteins, is one mechanism proposed to regulate plasma membrane solute permeabilities. The aims of our studies were to characterize endocytic processes in T84 cells and to investigate their regulation by known activators of Cl- secretion that are mediated by the cAMP second messenger cascade. Forskolin, an activator of adenylate cyclase, caused a marked inhibition of endocytic uptake of the fluid-phase marker horseradish peroxidase (HRP) and the adsorptive marker wheat germ agglutinin conjugated to HRP. Similar inhibition was obtained with vasoactive intestinal peptide, a secretagogue whose receptor is coupled to adenylate cyclase, and 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate, a membrane-permeable cAMP analogue. 1,9-Dideoxy-forskolin, a forskolin analogue that fails to activate adenylate cyclase, was without effect on endocytosis. Our data show that the net rate of endocytosis, as measured by fluid-phase uptake, is decreased by a cAMP-mediated mechanism. Because the number of Cl- channels or associated regulatory proteins in the plasma membrane reflects a balance between their exocytic insertion and endocytic retrieval, we propose that the cAMP-mediated decrease in endocytosis could contribute to the concomitant increase in plasma membrane Cl- permeability.
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PMID:Regulated endocytosis in a chloride secretory epithelial cell line. 131 84

The effects of forskolin, which is known as a direct activator of adenylate cyclase were studied on the slow inward calcium current (Isi) and phasic tension of frog atrial fibres. Forskolin induced a dose-dependent positive inotropic effect related to an increase in the slow inward calcium current. These effects, which were not reproduced by 1,9-dideoxyforskolin, seemed to result from an activation of adenylate cyclase. The action of forskolin was antagonized by adenosine and potentiated by phosphodiesterase inhibitors with the following order of potency: rolipram greater than theophylline greater than dipyridamole; M & B 22,948 was without influence. This study suggests that adenosine and rolipram might be suitable tools for studying the implication of cAMP in the modulation of contraction in frog atrium.
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PMID:Forskolin effects on slow inward current and phasic tension of frog atrial fibres: modulation by adenosine and phosphodiesterase inhibitors. 131 38

Elevation of intracellular cAMP is shown to increase the rate (V) and maximal extent of Ca2+ uptake by the dense tubules in intact human platelets. Elevation of [cAMP] was accomplished by preincubation with the adenylate cyclase activator forskolin or with dibutyryl-cAMP (Bt2-cAMP). The free concentration of Ca2+ in the dense tubular lumen ([Ca2+]dt) was monitored using the fluorescence of chlorotetracycline (CTC) according to protocols developed in this laboratory. The free cytoplasmic Ca2+ concentration ([Ca2+]cyt) was monitored in parallel experiments with quin2. Both [Ca2+]cyt and [Ca2+]dt were analyzed in terms of competition between pump and leak mechanisms in the plasma membrane (PM) and dense tubular membrane (DT). When platelets are incubated in media with approx. 1 microM external Ca2+, [Ca2+]cyt is approx. 50 nM and [Ca2+]dt is very low. When 2 mM external Ca2+ is added, [Ca2+]cyt rises to approx. 100 nM and the process of dense tubular Ca2+ uptake can be resolved. Forskolin (10 microM) and Bt2-cAMP increase the rate of dense tubular Ca2+ uptake (V) to 2.1 +/- 0.60 and 1.70 +/- 40 times control values (respectively). The agents also increase the final [Ca2+]dt to 1.70 +/- 0.21 and 1.72 +/- 0.60 times control values (respectively). Titrations with ionomycin (Iono) showed that the increase was due to an increase in the Vm of the dense tubular Ca2+ pump. With [Iono] = 500 nM, [Ca2+]cyt was raised to greater than or equal to 1.0 microM and Vm of the dense tubular pump was elicited. (At [Iono] = 1.0 microM, the final [Ca2+]dt values were degraded 15% due to shunting of Ca2+ uptake.) Analysis showed that forskolin (10 microM) and Bt2-cAMP (1 mM) increase the Vm by a factors of 1.56 +/- 40 and 1.56 +/- 40, respectively. Analysis showed that neither agent changed the Km of the pump significantly from its control value of 180 nM. Neither agent changed the rate constant for passive leakage of Ca2+ across the DT membrane (1.7 min-1).
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PMID:Stimulation of dense tubular Ca2+ uptake in human platelets by cAMP. 131 71

Forskolin, an adenylate cyclase activator, produces a reversible elevation of the endocochlear potential (EP) (Doi et al., 1990a). To determine whether strial Na(+)-K+ ATPase activity is essential for the forskolin-dependent EP elevation, we examined, by means of K(+)-selective microelectrodes, the effects of forskolin on the EP and the endolymphatic K+ activity ([K+]) while strial Na(+)-K+ ATPase was suppressed by ouabain. Perilymphatic perfusion with ouabain (10(-3) M) decreased the EP from 78.5 +/- 2.4 mV to -27.6 +/- 2.4 mV (N = 8) at 37.9 +/- 3.7 min after the start of perfusion and decreased the [K+] from 138.7 +/- 5.4 mM to 103.7 +/- 3.7 mM (N = 3). Successive perfusion with forskolin (2 x 10(-4) M) with ouabain (10(-3) M) increased the EP by 15.1 +/- 1.5 mV (N = 8) but did not influence the [K+] decrease from 101 +/- 3.6 mM to 95 +/- 1.3 mM (N = 3). Forskolin (2 x 10(-4) M) with ouabain (10(-3) M) without a preceding ouabain perfusion decreased the EP from 76.2 +/- 2.3 mV to -12.9 +/- 1.8 mV (N = 6) at 65.3 +/- 2.1 min after the start of perfusion. These results indicate that adenylate cyclase can modulate the EP in the absence of strial Na(+)-K+ ATPase activity and that adenylate cyclase activation can attenuate the EP drop induced by strial Na(+)-K+ ATPase suppression.
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PMID:Adenylate cyclase modulation of endocochlear potential during suppression of strial Na(+)-K+ ATPase. 131 96

beta-Adrenoceptor-mediated vasorelaxation is diminished in vessels from a variety of aged species including humans. This phenomenon was studied for the first time in cultured aorta smooth muscle cells (ASMC) from young (4- to 6-month) and old (24- to 26-month) F-344 rats. Cyclic AMP (cAMP) accumulation was assessed following isoproterenol and forskolin stimulations in primary cultures and after 1-4 passages of aorta smooth muscle cells. Isoproterenol and forskolin increased cAMP accumulation 6- and 10-fold, respectively, in primary cultures from young rats. Isoproterenol stimulation was reduced markedly in passaged cells. Forskolin stimulation was unaffected, indicating passage-related phenotypic changes in receptor-mediated stimulation, but not in post-receptor adenylate cyclase activation. The response to isoproterenol was diminished in old animals, but that to forskolin was unaltered. Thus, cultured ASMC from F-344 rats are highly responsive to beta-adrenoceptor stimulation and demonstrate age-related changes, but undergo phenotypic modulation during passage.
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PMID:Beta-adrenergic responsiveness in cultured aorta smooth muscle cells. Effects of subculture and aging. 131 46


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