Phosphoinositide 3-kinaseγ (PI3Kγ) controls L-type calcium current (ICa,L) through its positive modulation of type-3 phosphodiesterase (PDE3)

Themodulation of L-type calcium current (I-Ca,I-L) is mainly due to mediators acting through activation of G protein-coupled receptors (GPCR) and different protein kinases; among them, phosphoinositide 3-kinase gamma (PI3K gamma) has been recently discovered to play an important role in the regulation of cardiac contractility and beta-adrenergic signal transduction. Recent reports have demonstrated that, in the heart, different subtypes of beta-adrenergic receptors are coupled to both G(i) and/or G(s) proteins. While beta(1)-adrenergic receptors (beta 1-AR) couple only to G(s) and evoke a strong I-Ca,I-L, beta 2-adrenergic receptors (beta 2-AR)can activate both G,and Gi proteins and trigger only a limited I-Ca,I-L. Here we demonstrate that (i) PI3K gamma(-/-) ventricular myocytes are characterized by an higher basal I-Ca,I-L density, even if the responsiveness of adenylyl cyclase to Forskolin is comparable to that observed in PI3K gamma(+/+) cardiomyocytes; (ii) both in basal conditions and after beta-AR stimulation, the activity of phosphodiesterase (PDE) type 3 depends on PI3K gamma; (iii) in PI3K gamma(-/-) cardiac myocytes, specific stimulation of beta 2-AR is followed by a increase in I-Ca,I-L stronger than in wild-type controls. Taken together, our results suggest that the higher values of I-Ca,I-L observed both in basal conditions and after beta-AR stimulation in PI3K gamma(-/-) ventricular myocytes are mainly due to a positive modulation of PDE3 activity exerted by PI3K gamma. As observed in PI3K gamma(-/-) neonatal cardiomyocytes, cells lacking PI3K gamma are more sensitive to Stimulation of beta 2-adrenergic receptors.