G protein-coupled receptors and their regulation

Seven membrane spanning domain G protein-coupled receptors represent the most ubiquitous and diverse group of membrane bound signaling receptors. Their function is regulated by two families of molecules, the G protein-coupled receptor kinases and the ß-arrestins which function in concert to desensitize receptor function after stimulation. The kinases phosphorylate only the activated forms of the receptor leading to the binding of ß-arrestin molecules which sterically interdict signal transduction to the G proteins. Some of the kinases such as the ß-adrenergic receptor kinase are largely cytosolic but are translocated to the membranes by interaction with membrane lipids such as PIP2 and membrane anchored proteins such as the Gß7 subunit complex. Different Gßy subunits associate with different members of the GRK family imparting a level of specificity to the interaction of these kinases with the receptors, ß-arrestin binding to the receptors also promotes their internalization into clathrin coated pits. Within internalized endosomes the receptors are dephosphorylated and resensitized by a special G protein-coupled receptor phosphatase, the activity of which toward the receptor is regulated by the uniquely low endosomal pH. Recent experiments also indicate that both ß-arrestin and the GRKs play previously unsuspected roles in cellular signaling cascades and these will be discussed.

Duke Scholars

Author Robert J. Lefkowitz Medicine, Cardiology