Phosphoinositide 3-kinasegamma (PI3Kgamma) 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-kinasegamma (PI3Kgamma) 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 Gi and/or Gs proteins. While beta1-adrenergic receptors (beta1-AR) couple only to Gs and evoke a strong ICa,L, beta2-adrenergic receptors (beta2-AR) can activate both Gs and Gi proteins and trigger only a limited ICa,L. Here we demonstrate that (i) PI3Kgamma-/- 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 PI3Kgamma+/+ cardiomyocytes; (ii) both in basal conditions and after beta-AR stimulation, the activity of phosphodiesterase (PDE) type 3 depends on PI3Kgamma; (iii) in PI3Kgamma-/- cardiac myocytes, specific stimulation of beta2-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 beta-AR stimulation in PI3Kgamma-/- ventricular myocytes are mainly due to a positive modulation of PDE3 activity exerted by PI3Kgamma. As observed in PI3Kgamma-/- neonatal cardiomyocytes, cells lacking PI3Kgamma are more sensitive to stimulation of beta2-adrenergic receptors.
Marcantoni
Andrea
A
Dipartimento di Neuroscienze, Università degli Studi di Torino, Torino, Italy.
Levi
Renzo Cesare
RC
Gallo
Maria Pia
MP
Hirsch
Emilio
E
Alloatti
Giuseppe
G
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D005576:Colforsin / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D005260:Female; D006352:Heart Ventricles / Q000166:cytology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction
D020746:Calcium Channels, L-Type; D007527:Isoenzymes; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3