Posts Tagged: smooth muscle myocytes

PI3K and Calcium Signaling in Cardiovascular Disease

PI3K and Calcium Signaling in Cardiovascular Disease

Alessandra Ghigo, Muriel Laffargue, Mingchuan Li, Emilio Hirsch

Class I PI3Ks (phosphoinositide 3-kinases). Class I PI3Ks are obligate heterodimers composed by a p110 catalytic module and an adaptor subunit. Depending on the nature of the adaptor and of the activating membrane receptor, class I PI3Ks can be subgrouped into class IA and IB. Class IA includes PI3Kα, β, and δ, which are coupled to a p85 regulatory subunit and are engaged by tyrosine kinase receptors (RTKs). On the contrary, the unique member of class IB, PI3Kγ, binds to either p101 or p87 that, by tethering p110γ to the Gβγ subunit of G protein-coupled receptors (GPCRs), ensure the full enzyme activation. All class I isoenzymes phosphorylate PIP2 PtdIns(4,5)P2 to produce PIP3 that, in turn, serves as a docking site for intracellular effectors carrying a lipid-binding domain, such as Akt (protein kinase B). Activated Akt ultimately initiates a wide spectrum of biological events, ranging from proliferation, survival, and metabolic regulation. [Powerpoint File]

PI3K and Calcium Signaling in Cardiovascular Disease

PI3K and Calcium Signaling in Cardiovascular Disease

Alessandra Ghigo, Muriel Laffargue, Mingchuan Li, Emilio Hirsch

PI3K (phosphoinositide 3-kinase)-mediated compartmentalization of β-adrenergic receptors-dependent Ca2+ responses in cardiomyocytes. Class IB PI3Kγ restrains Ca2+ signaling in response to β-adrenergic stimuli via a kinase-unrelated mechanism. This relies on the ability of PI3Kγ to anchor PDE (phosphodiesterase)3 or 4 to their activator PKA in specific subcellular compartments and to promote PKA-mediated activation of PDEs (active PDE3/4). The ensuing cyclic AMP (cAMP) reduction limits PKA-mediated phosphorylation and activation of Ca2+-handling proteins, including L-type Ca2+ channel (LTCC) and PLN (phospholamban; left). In heart failure, a functional decay in PI3Kγ-directed protein–protein interactions limits PDE activity (inactive PDE3/4), leading to abnormal cAMP accumulation and uncontrolled PKA activity close to LTCC and PLN, which culminate in arrhythmogenic Ca2+ release events (right). PLN indicates phospholamban; and SR, sarcoplasmic reticulum. [Powerpoint File]