Identification of the macromolecular complex responsible for PI3Kgamma-dependent regulation of cAMP levels.
PI3Kgamma is a phosphoinositide 3-kinase characterized by both lipid and protein kinase activity. It is activated by G-protein-coupled receptors and is predominantly expressed in leucocytes; in addition, recent work showed its presence in the heart and its involvement in regulating cardiac functions. In this tissue, PI3Kgamma acts as a negative modulator of contractility, by decreasing cAMP concentration through a kinase-independent mechanism. Indeed, whereas PI3Kgamma-deficient mice show an abnormal cAMP elevation, cAMP levels in knock-in mouse mutants, expressing a kinase-dead PI3Kgamma, are comparable with wild-type controls. PI3Kgamma regulates cardiac cAMP homoeostasis by forming a macromolecular complex containing PDE3B (phosphodiesterase 3B). In this complex, PI3Kgamma could regulate PDE3B activity through protein kinase A, a PDE activator.
Perino
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A
Department of Genetics, Biology and Biochemistry, University of Torino, Via Santena 5bis, 10126 Torino, Italy. alessia.perino@libero.it
Ghigo
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A
Damilano
F
F
Hirsch
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E
D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000242:Cyclic AMP / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction
D007527:Isoenzymes; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse