Phosphoinositide 3-kinase γ Regulates Cardiac Contractility by Locally Controlling Cyclic Adenosine Monophosphate Levels

Class I phosphoinositide 3-kinases (PI3Ks) are enzymes with both protein and lipid kinase activities that regulate important cellular functions in many tissues. In the heart, subclass IA PI3Ks (mainly PI3Kα) regulate cell growth, apoptosis, cell division and cell size, whereas PI3Kγ, the only member of subclass IB, has been shown to regulate cardiac contractility. We have shown that the loss of PI3Kγ  (PI3Kγ^−/− mice) enhances cardiac excitation–contraction coupling by modulating cyclic adenosine monophosphate (cAMP) levels in subcellular domains containing the sarcoplasmic reticulum. Specifically, PI3Kγ^−/− mice show enhanced sarcoplasmic reticulum Ca²⁺ cycling in association with increased cAMP. Surprisingly, L-type Ca²⁺ current, a prototypic target of cAMP-dependent protein kinase A phosphorylation, is largely unchanged in PI3Kγ^−/− mice. In this article, we discuss the consequences and implications of cAMP compartmentation in cardiomyocytes. We also review the different roles of PI3Kγ in the heart, particularly as they relate to cardiac contractility, intracellular cAMP levels, and the regulation of β-adrenergic receptor signaling in physiologic and pathologic states.

Abbreviations: AC, Adenylyl cyclase, AKAP, A-kinase anchoring protein, β-AR, β-Adrenergic receptors, ECC, Excitation–contraction coupling, I_Ca,L, L-type Ca²⁺ current, ISO, Isoproterenol, PDE, Phosphodiesterase, PI3K, Phosphoinositide 3-kinase, PIP₂, Phosphatidylinositol-4,5-bisphosphate, PIP₃, Phosphatidylinositol-3,4,5-triphosphate, PKA, Protein kinase A, PKB/Akt, Protein kinase B, PLN, Phospholamban, RyR₂, Ryanodine receptor type 2, SERCA-2a, Sarcoendoplasmic reticulum Ca²⁺-ATPase pump type 2a, SR, Sarcoplasmic reticulum