Phosphoinositide 3-kinase gamma 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 PI3Kalpha) regulate cell growth, apoptosis, cell division and cell size, whereas PI3Kgamma, the only member of subclass IB, has been shown to regulate cardiac contractility. We have shown that the loss of PI3Kgamma (PI3Kgamma(-/-) mice) enhances cardiac excitation-contraction coupling by modulating cyclic adenosine monophosphate (cAMP) levels in subcellular domains containing the sarcoplasmic reticulum. Specifically, PI3Kgamma(-/-) mice show enhanced sarcoplasmic reticulum Ca(2+) cycling in association with increased cAMP. Surprisingly, L-type Ca(2+) current, a prototypic target of cAMP-dependent protein kinase A phosphorylation, is largely unchanged in PI3Kgamma(-/-) mice. In this article, we discuss the consequences and implications of cAMP compartmentation in cardiomyocytes. We also review the different roles of PI3Kgamma in the heart, particularly as they relate to cardiac contractility, intracellular cAMP levels, and the regulation of beta-adrenergic receptor signaling in physiologic and pathologic states.
Kerfant
Benoit-Gilles
BG
Department of Physiology and Medicine, University of Toronto, Heart & Stroke/Richard Lewar Centre, Toronto, Ontario, Canada M5S 3E2.
Rose
Robert A
RA
Sun
Hui
H
Backx
Peter H
PH
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002451:Cell Compartmentation; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000242:Cyclic AMP / Q000378:metabolism*; D006331:Heart Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction
D020746:Calcium Channels, L-Type; D007527:Isoenzymes; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse