PI3Kgamma in the Heart: Kinase-dependent and -Independent Functions in Contractility and Hypertrophy

摘要

Cardiac contractility is regulated by G protein-coupled receptors (GPCRs) that modulate the production of a wide variety of second messenger molecules. Among these, cAMP and Ca~(2+) are the best characterized (Rockman et al., 2002). However, it was recently found that phospho-rylated lipids like phosphatidylinositol (3,4,5)-trisphosphate (PIP3) are also involved, especially in pathologic situations like hypertrophy and failure (Rockman et al., 2002). PIP3 is the product of a family of enzymes known as phosphoinositide 3-kinases (PI3Ks) (Vanhaesebroeck et al., 2001) which are widely expressed in different tissues, are activated by GPCR as well as tyrosine kinase receptors and are responsible for a large variety of cellular responses. It has been previously reported that, in the heart, the GPCR-activated phosphoinositide 3-kinase (gamma)(PI3K(gamma)) negatively controls contractility by reducing cAMP concentration (Crackower et al., 2002) and by modulating NOS3-dependent NO production (Alloatti et al., 2003). PI3K(gamma) has also been show to stimulate b-adrenergic receptor shedding fro the plasma membrane through a mechanism involving a direct association with GRK2 which desensitizes the receptor but also correctly localizes PI3Kythat in turn potentiates the internalization process (Prasad et al., 2003).