Agonist-dependent recruitment of phosphoinositide 3-kinase to the membraneby beta-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 l iberated G beta gamma subunits. Subsequent internalization of agonist-occup ied receptors occurs as a result of the binding of beta -arrestin to the ph osphorylated receptor followed by interaction with the AP2 adaptor and clat hrin proteins. Receptor internalization is known to require D-3 phosphoinos itides that are generated by the action of phosphoinositide 3-kinase. Phosp hoinositide 3-kinases form a family of lipid kinases that couple signals vi a receptor tyrosine kinases and G-protein-coupled receptors, The molecular mechanism by which phosphoinositide 3-kinase acts to promote beta -adrenerg ic receptor internalization is not well understood. In the present investig ation we demonstrate a novel finding that beta -adrenergic receptor kinase 1 and phosphoinositide 3-kinase form a cytosolic complex, which leads to be ta -adrenergic receptor kinase 1-mediated translocation of phosphoinositide 3-kinase to the membrane in an agonist-dependent manner. Furthermore, agon ist-induced translocation of phosphoinositide 3-kinase results in rapid int eraction with the receptor, which is of functional importance, since inhibi tion of phosphoinositide 3-kinase activity attenuates beta -adrenergic rece ptor sequestration. Therefore, agonist-dependent recruitment of phosphoinos itide 3-kinase to the membrane is an important step in the process of recep tor sequestration and links phosphoinositide 3-kinase to G-protein-coupled receptor activation and sequestration.