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

The modulation of L‐type calcium current (ICa,L) is mainly due to mediators acting through activation of G protein‐coupled receptors (GPCR) and different protein kinases; among them, phosphoinositide 3‐kinaseγ (PI3Kγ) has been recently discovered to play an important role in the regulation of cardiac contractility and β‐adrenergic signal transduction. Recent reports have demonstrated that, in the heart, different subtypes of β‐adrenergic receptors are coupled to both Gi and/or Gs proteins. While β1‐adrenergic receptors (β1‐AR) couple only to Gs and evoke a strong ICa,L, β2‐adrenergic receptors (β2‐AR) can activate both Gs and Gi proteins and trigger only a limited ICa,L. Here we demonstrate that (i) PI3Kγ−/− ventricular myocytes are characterized by an higher basal ICa,L density, even if the responsiveness of adenylyl cyclase to Forskolin is comparable to that observed in PI3Kγ+/+ cardiomyocytes; (ii) both in basal conditions and after β‐AR stimulation, the activity of phosphodiesterase (PDE) type 3 depends on PI3Kγ; (iii) in PI3Kγ−/− cardiac myocytes, specific stimulation of β2‐AR is followed by a increase in ICa,L stronger than in wild‐type controls. Taken together, our results suggest that the higher values of ICa,L observed both in basal conditions and after β‐AR stimulation in PI3Kγ−/− ventricular myocytes are mainly due to a positive modulation of PDE3 activity exerted by PI3Kγ. As observed in PI3Kγ−/− neonatal cardiomyocytes, cells lacking PI3Kγ are more sensitive to stimulation of β2‐adrenergic receptors. J. Cell. Physiol. 206: 329–336, 2006. © 2005 Wiley‐Liss, Inc.