Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The age-dependent relationships between glucagon-induced alterations in myocardial mechanics and adenylate cyclase activity in fetal and newborn lambs and adult sheep were evaluated. Glucagon substantially augmented the force of contraction of ventricular myocardium isolated from the adult but not from the fetus or newborn. Similarly, substantial increases in the spontaneous frequency of contraction and tension were observed in adult atrial strips, but not in the fetus or newborn. Comparable activities of phosphodiesterase were observed in extracts from fetal and adult myocardium and were unaltered by the addition of glucagon. Adenylate cyclase activity in adult myocardial homogenate and particulate fractions was comparable to that of fetal tissue. Glucagon stimulation of the particulate fraction produced no change in fetal adenylate cyclase activity whereas a 43% increase in activity was observed in preparations from adult tissue. Sodium fluoride and epinephrine augmented adenylate cyclase activity in both fetal and adult myocardium. Thus, glucagon produced age-dependent, parallel changes in heart rate, active tension development, and particulate fraction adenylate cyclase activity, suggesting that these chronotropic and inotropic responses are indeed mediated by adenylate cyclase and that lack of response in the fetus reflects the absence of mature glucagon receptor sites.
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PMID:Age-dependent mechanical and biochemical responses to glucagon. 18 Aug 16

The effect of bile acids on adenosine 3',5'-cyclic monophosphate (cAMP) synthesis was investigated in isolated hamster hepatocytes. Bile acids had no direct effect on cAMP production. However, ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid inhibited, by approximately 45%, cAMP formation induced by concentrations of glucagon greater than 1 nM, with a respective half-maximum inhibitory effect observed at 4 +/- 2 microM. Similar inhibition was observed with phorbol 12-myristate 13-acetate (PMA). Chenodeoxycholic, murocholic, and taurodeoxycholic acids were the next most potent bile acids. Taurolithocholic acid was 100-fold less potent than UDCA, whereas both ursocholic and taurocholic acids had no effect at concentrations up to 0.5 mM. Neither bile acids nor PMA affected either the binding of glucagon to its receptor, the cAMP-dependent phosphodiesterase, adenylate cyclase, or the inhibitory and stimulatory (Gs) GTP-binding proteins. The inhibitory effect of PMA and UDCA on glucagon-induced cAMP synthesis was abolished in the presence of the protein kinase C (PKC) inhibitor, staurosporine. Furthermore, UDCA induced PKC translocation from cytosol to membrane and stimulated phosphorylation of an 80-kDa protein substrate for PKC. In conclusion, mediated by PKC activation, bile acids inhibit glucagon-induced cAMP synthesis by uncoupling the glucagon receptor and Gs.
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PMID:Ursodeoxycholic acid inhibits glucagon-induced cAMP formation in hamster hepatocytes: a role for PKC. 786 27

Glucagon elicited a profound increase in the intracellular cAMP concentration of COS-7 cells which had been transiently transfected with a cDNA encoding the rat glucagon receptor and under conditions where cAMP phosphodiesterase activity was fully inhibited. This was achieved in a dose-dependent fashion with an EC50 of 1.8+/-0.4 nM glucagon. In contrast with previous observations made using hepatocytes [Heyworth, Whetton, Kinsella and Houslay (1984) FEBS Lett. 170, 38-42], treatment of transfected COS-7 cells with PMA did not inhibit the ability of glucagon to increase intracellular cAMP levels. PMA-mediated inhibition was not conferred by treatment with okadaic acid, nor by co-transfecting cells with cDNAs encoding various protein kinase C isoforms (PKC-alpha, PKC-betaII and PKC-epsilon) or with the PMA-activated G-protein-receptor kinases GRK2 and GRK3. In contrast, PMA induced the marked inhibition of glucagon-stimulated cAMP production in COS-7 cells that had been co-transfected with a cDNA encoding protein kinase D (PKD). Such inhibition was not due to an action on the catalytic unit of adenylate cyclase, as forskolin-stimulated cAMP production was unchanged by PMA treatment of COS cells that had been co-transfected with both the glucagon receptor and PKD. PKD transcripts were detected in RNA isolated from hepatocytes but not from COS-7 cells. Transcripts for GRK2 were present in hepatocytes but not in COS cells, whereas transcripts for GRK3 were not found in either cell type. It is suggested that PKD may play a role in the regulation of glucagon-stimulated adenylate cyclase.
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PMID:Co-transfection with protein kinase D confers phorbol-ester-mediated inhibition on glucagon-stimulated cAMP accumulation in COS cells transfected to overexpress glucagon receptors. 929 Nov 30

Since many isoforms of adenylyl cyclase and adenosine 3', 5'-monophosphate (cAMP) phosphodiesterase have been cloned, it is likely that receptors of each hormone have a specific combination of these isoforms. Types I, III and VIII adenylyl cyclases are reported to be stimulated by Ca(2+)-calmodulin, type I phosphodiesterase by Ca(2+)-calmodulin, but types IV and VII (cAMP-specific) phosphodiesterases by Co2+. In the present study, we examined different effects of Ca2+ and Co2+ on hormone-induced cAMP response in the isolated perfused rat liver.The removal of Ca2+ from the perfusion medium (0 mM CaCl(2 ) + 0.5 mM EGTA) did not affect glucagon (0.1 nM)-responsive cAMP but reduced secretin (1 nM)-, vasoactive intestinal polypeptide (VIP, 1-10 nM)- and forskolin (1 microM)-responsive cAMP considerably. The addition of 1 mM CoCl2 reduced glucagon- and secretin-responsive cAMP considerably, forskolin-responsive cAMP partly, did not affect 1 nM VIP-responsive cAMP, but enhanced 10 nM VIP-responsive cAMP. Forskolin- and VIP-responsive cAMP was greater in the combination (0 mM CaCl(2) + 0.5 mM EGTA + 3 mM CoCl2) than in the Ca(2+)-free perfusion alone. These results suggest that secretin, VIP1 and VIP2 receptors are linked to Ca(2+)-calmodulin-sensitive adenylyl cyclase; glucagon receptor to Ca(2+)-calmodulin-insensitive adenylyl cyclase; VIP1 receptor to Ca(2+)-calmodulin-dependent phosphodiesterase; glucagon, secretin and VIP2 receptors to cAMP-specific phosphodiesterase, respectively, in the rat liver.
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PMID:Hormone-specific combinations of isoforms of adenylyl cyclase and phosphodiesterase in the rat liver. 1125 14

Signaling pathways targeting mitochondria are poorly understood. We here examine phosphorylation by the cAMP-dependent pathway of subunits of cytochrome c oxidase (COX), the terminal enzyme of the electron transport chain. Using anti-phospho antibodies, we show that cow liver COX subunit I is tyrosinephosphorylated in the presence of theophylline, a phosphodiesterase inhibitor that creates high cAMP levels, but not in its absence. The site of phosphorylation, identified by mass spectrometry, is tyrosine 304 of COX catalytic subunit I. Subunit I phosphorylation leads to a decrease of V(max) and an increase of K(m) for cytochrome c and shifts the reaction kinetics from hyperbolic to sigmoidal such that COX is fully or strongly inhibited up to 10 mum cytochrome c substrate concentrations, even in the presence of allosteric activator ADP. To assess our findings with the isolated enzyme in a physiological context, we tested the starvation signal glucagon on human HepG2 cells and cow liver tissue. Glucagon leads to COX inactivation, an effect also observed after incubation with adenylyl cyclase activator forskolin. Thus, the glucagon receptor/G-protein/cAMP pathway regulates COX activity. At therapeutic concentrations used for asthma relief, theophylline causes lung COX inhibition and decreases cellular ATP levels, suggesting a mechanism for its clinical action.
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PMID:cAMP-dependent tyrosine phosphorylation of subunit I inhibits cytochrome c oxidase activity. 1555 77

This study evaluates the inotropic responses to glucagon in electrically driven isolated left and right atria as well as in right ventricular strips of rat heart. For comparison, the contractile effects resulting from stimulating beta-adrenoceptors with isoprenaline in atrial and ventricular tissues were also obtained. Glucagon (0.01-1 microM) produces a concentration-dependent positive inotropic effect in ventricular but not in atrial myocardium. Isoprenaline, however, increases contractility both in atrial and ventricular tissues. The nonselective phosphodiesterase (PDE) inhibitor 3-isobutylmethylxantine (IBMX, 10 microM) enhances the contractile effect of glucagon on ventricular myocardium. However, glucagon still failed to increase contractility in atrial myocardium in the presence of 10 microM, IBMX. Also, in left atria of rats pretreated with pertussis toxin, glucagon did not produce any positive inotropic effect, either alone or in the presence of 10 microM, IBMX. Western blotting analysis indicates that glucagon receptors expression is 5 times higher in ventricular than in atrial myocardium. Taken together, these results indicate that the lack of inotropic effect of glucagon in atrium is not due to Gi protein or PDEs activity but seems to be a consequence of a lower glucagon receptor density in this tissue.
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PMID:Glucagon increases contractility in ventricle but not in atrium of the rat heart. 1847 67