Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by β-adrenergic receptor kinase 1 -: A role in receptor sequestration

Agonist-dependent desensitization of the beta -adrenergic receptor requires translocation and activation of the beta -adrenergic receptor kinase1 by liberated G beta gamma subunits. Subsequent internalization of agonist-occupied receptors occurs as a result of the binding of beta -arrestin to the phosphorylated receptor followed by interaction with the AP2 adaptor and clathrin proteins. Receptor internalization is known to require D-3 phosphoinositides that are generated by the action of phosphoinositide 3-kinase. Phosphoinositide 3-kinases form a family of lipid kinases that couple signals via receptor tyrosine kinases and G-protein-coupled receptors, The molecular mechanism by which phosphoinositide 3-kinase acts to promote beta -adrenergic receptor internalization is not well understood. In the present investigation we demonstrate a novel finding that beta -adrenergic receptor kinase 1 and phosphoinositide 3-kinase form a cytosolic complex, which leads to beta -adrenergic receptor kinase 1-mediated translocation of phosphoinositide 3-kinase to the membrane in an agonist-dependent manner. Furthermore, agonist-induced translocation of phosphoinositide 3-kinase results in rapid interaction with the receptor, which is of functional importance, since inhibition of phosphoinositide 3-kinase activity attenuates beta -adrenergic receptor sequestration. Therefore, agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane is an important step in the process of receptor sequestration and links phosphoinositide 3-kinase to G-protein-coupled receptor activation and sequestration.