2004
DOI: 10.1074/jbc.m314238200
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Direct Inhibition of Type 5 Adenylyl Cyclase Prevents Myocardial Apoptosis without Functional Deterioration

Abstract: Adenylyl cyclase, a major target enzyme of ␤-adrenergic receptor signals, is potently and directly inhibited by P-site inhibitors, classic inhibitors of this enzyme, when the enzyme catalytic activity is high. Unlike ␤-adrenergic receptor antagonists, this is a non-or uncompetitive inhibition with respect to ATP. We have examined whether we can utilize this enzymatic property to regulate the effects of ␤-adrenergic receptor stimulation differentially. After screening multiple new and classic compounds, we foun… Show more

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Cited by 94 publications
(107 citation statements)
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“…These results suggest that type 5 adenylyl cyclase in the heart may play a minor role in the production of cyclic AMP under physiological condition. However, inhibitory effect of vidarabine on type 5 adenylyl cyclase was confirmed in the presence of isoproterenol, forskolin and/or guanosine 5'-[γ-thio] triphospahate (GTPγS) (Iwatsubo et al, 2004(Iwatsubo et al, , 2012Braeunig et al, 2013). One can speculate that vidarabine might be at least in part expected to improve the pathophysiology of congestive heart failure in the presence of increased adrenergic tone, whereas modification will not be exerted during the absence of such pathological situation, which may become advantage over the conventional Na + channel inhibitors and/or β blockers.…”
Section: Cardiohemodynamic Effectsmentioning
confidence: 99%
See 1 more Smart Citation
“…These results suggest that type 5 adenylyl cyclase in the heart may play a minor role in the production of cyclic AMP under physiological condition. However, inhibitory effect of vidarabine on type 5 adenylyl cyclase was confirmed in the presence of isoproterenol, forskolin and/or guanosine 5'-[γ-thio] triphospahate (GTPγS) (Iwatsubo et al, 2004(Iwatsubo et al, , 2012Braeunig et al, 2013). One can speculate that vidarabine might be at least in part expected to improve the pathophysiology of congestive heart failure in the presence of increased adrenergic tone, whereas modification will not be exerted during the absence of such pathological situation, which may become advantage over the conventional Na + channel inhibitors and/or β blockers.…”
Section: Cardiohemodynamic Effectsmentioning
confidence: 99%
“…Vidarabine in a dose of 10-15 mg/kg is clinically recommended for the treatment of herpes simplex encephalitis in the interview form (Sep. 2011, ver.3) from the manufacturer. Moreover, vidarabine has been reported to inhibit type 5 adenylyl cyclase (Iwatsubo et al, 2004), thus to improve the left ventricular ejection fraction and survival rate of experimental mice models of congestive heart failure (Iwatsubo et al, 2012). Recently, vidarabine was shown to suppress atrial fibrillation of mice induced by transesophageal atrial burst pacing during isoproterenol infusion (Suita et al, 2014).…”
Section: Introductionmentioning
confidence: 99%
“…Western blot analysis was performed as we described previously (20). Cells were lysed and sonicated in lysis buffer containing 25 mM Tris ⅐ HCl (pH 7.5), 150 mM NaCl, 5 mM MgCl2, 1% Nonidet P-40, 1 mM dithiothreitol, 5% glycerol, phosphatase inhibitor (Sigma), protease inhibitor cocktail (Sigma), and 1 mM NaF.…”
Section: Methodsmentioning
confidence: 99%
“…The same differences between the adenine and sugar binding pockets of sAC and tmACs, which decreases AC's affinity for ATP, should also explain its diminished sensitivity to inhibition by P-site ligands. 117 Interestingly, a new series of P-site inhibitors, such as the compoundPMC-6 (1R,4R-3-(6-aminopurin-9-yl)-cyclopentanecarboxylic acid hydroxyamide), contain a metal chelating moiety 118,119 and can discriminate between some tmAC isoforms; 119 PMC-6 inhibits type II and III modestly, but tmAC V with high potency.…”
Section: Substrate Atp Atp-analogs and P-site Inhibitorsmentioning
confidence: 99%