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

Phosphoinositide 3-kinase (PI3K) gamma has been implicated in a vast array of physiological settings including the activation of different leukocyte species and the regulation of myocardial contractility. Activation of PI3Kgamma is primarily mediated by Gbetagamma subunits of heterotrimeric G proteins, which are recognized by a p101 regulatory subunit. Here, we describe the identification and characterization of a novel regulatory subunit of PI3Kgamma, which we termed p87(PIKAP) (PI3Kgamma adapter protein of 87 kDa). It is homologous to p101 in areas that we have recently shown that they mediate binding to the catalytic p110gamma subunit and to Gbetagamma. Like p101, p87(PIKAP) binds to both p110gamma and Gbetagamma and mediates activation of p110gamma downstream of G protein-coupled receptors. In contrast to p101, p87(PIKAP) is highly expressed in heart and may therefore be crucial to PI3Kgamma cardiac function. Moreover, p87(PIKAP) and p101 are both expressed in dendritic cells, macrophages, and neutrophils, raising the possibility of regulatory subunit-dependent differences in PI3Kgamma signaling within the same cell type. We further provide evidence that p87(PIKAP) physically interacts with phosphodiesterase (PDE) 3B, suggesting that p87(PIKAP) is also involved in the recently described noncatalytic scaffolding interaction of p110gamma with PDE3B. However, coexpression of PDE3B and PI3Kgamma subunits was not sufficient to reconstitute the regulatory effect of PI3Kgamma on PDE3B activity observed in heart, implying further molecules to be present in the complex regulating PDE3B in heart.
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PMID:Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase gamma that is highly expressed in heart and interacts with PDE3B. 1647 36

We recently showed that phosphoinositide-3-kinase-gamma-deficient (PI3Kgamma(-/-)) mice have enhanced cardiac contractility attributable to cAMP-dependent increases in sarcoplasmic reticulum (SR) Ca(2+) content and release but not L-type Ca(2+) current (I(Ca,L)), demonstrating PI3Kgamma locally regulates cAMP levels in cardiomyocytes. Because phosphodiesterases (PDEs) can contribute to cAMP compartmentation, we examined whether the PDE activity was altered by PI3Kgamma ablation. Selective inhibition of PDE3 or PDE4 in wild-type (WT) cardiomyocytes elevated Ca(2+) transients, SR Ca(2+) content, and phospholamban phosphorylation (PLN-PO(4)) by similar amounts to levels observed in untreated PI3Kgamma(-/-) myocytes. Combined PDE3 and PDE4 inhibition caused no further increases in SR function. By contrast, only PDE3 inhibition affected Ca(2+) transients, SR Ca(2+) loads, and PLN-PO(4) levels in PI3Kgamma(-/-) myocytes. On the other hand, inhibition of PDE3 or PDE4 alone did not affect I(Ca,L) in either PI3Kgamma(-/-) or WT cardiomyocytes, whereas simultaneous PDE3 and PDE4 inhibition elevated I(Ca,L) in both groups. Ryanodine receptor (RyR(2)) phosphorylation levels were not different in basal conditions between PI3Kgamma(-/-) and WT myocytes and increased in both groups with PDE inhibition. Our results establish that L-type Ca(2+) channels, RyR(2), and SR Ca(2+) pumps are regulated differently in distinct subcellular compartments by PDE3 and PDE4. In addition, the loss of PI3Kgamma selectively abolishes PDE4 activity, not PDE3, in subcellular compartments containing the SR Ca(2+)-ATPase but not RyR(2) or L-type Ca(2+) channels.
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PMID:PI3Kgamma is required for PDE4, not PDE3, activity in subcellular microdomains containing the sarcoplasmic reticular calcium ATPase in cardiomyocytes. 1761 71