Phosphoinositide 3-kinase gamma: kinase-dependent and -independent activities in cardiovascular function and disease.
Cardiac function is controlled by GPCRs (G-protein-coupled receptors) which exert their function by triggering numerous signalling pathways, including the activation of PI3K (phosphoinositide 3-kinase). The GPCR-activated PI3Kgamma is weakly expressed in the heart, but the deletion of its expression in mice causes remarkable phenotypes. Indeed, the lack of PI3Kgamma does not modify heart rate and blood pressure, but does increase contractility, particularly in response to stimuli that enhance cardiac contractile force, such as catecholamines. Consistently, treatment of mutant cardiomyocytes with beta-adrenergic agonists causes an abnormal increase in the elevation of cAMP production. On the other hand, PI3Kgamma appears to play a role in mediating the contractile depression exerted by other GPCR agonists, such as PAF (platelet-activating factor), that are released in pathological conditions, such as after an ischaemic insult. The receptor for PAF coupled to G(i) activates PI3Kgamma, which, in turn, is essential to promote Akt phosphorylation, NOSIII (nitric oxide synthase isoform III) activation and the production of nitric oxide, a well characterized cardiodepressing agent. As a whole, PI3Kgamma appears to negatively control cardiac contractility through different signalling mechanisms, thus becoming a possible drug target for the treatment of critical human cardiac pathologies, such as infarction or heart failure.
Alloatti
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G
Dipartimento di Biologia Animale e dell'Uomo e Istituto Nazionale per la Fisica della Materia, Università di Torino, Turin, Italy.
Montrucchio
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G
Lembo
G
G
Hirsch
E
E
D000818:Animals; D002319:Cardiovascular System / Q000201:enzymology*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D006331:Heart Diseases / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia; D009569:Nitric Oxide / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology*; D010972:Platelet Activating Factor / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
D007527:Isoenzymes; D010972:Platelet Activating Factor; D043562:Receptors, G-Protein-Coupled; D009569:Nitric Oxide; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse