Mechanisms of β-Adrenergic Receptor Desensitization and Resensitization

Abstract

Desensitization represents the summation of several different processes, including receptor phosphorylation, receptor sequestration (defined as the agonist-induced translocation of receptor away from the plasma membrane), enhanced degradation of intracellular messengers, and degradation of receptor protein. Rapid receptor desensitization, however, appears to be mediated by uncoupling of the receptor from its respective G protein, a consequence of receptor phosphorylation. In the case of the β2-adrenergic receptor (β2AR), phosphorylation by two distinct classes of serine-threonine kinases leads to receptor desensitization. The first class, the second-messenger—dependent kinases—cyclic adenosine monophosphate (CAMP)-dependent protein kinase (PKA) and protein kinase C—phosphorylate and directly uncouple β2AR from Gs. Because these kinases phosphorylate receptors in an agonist-independent manner, this process permits cross-talk between receptor families. The second class of enzymes, the G protein-coupled receptor kinases (GRKs), plays a highly specialized role in receptor desensitization because only agonist-occupied receptors serve as substrates for these enzymes. In the case of GRKs, the very signal that promotes activation of the G protein and the effector (that is, ligand binding) also promotes the desensitization of that specific receptor. Once uncoupled from the G protein, receptor function can be restored only by receptor dephosphorylation, a process termed resensitization. The phosphatases and regulatory mechanisms involved in this resensitization process have only recently begun to be elucidated and are included in this chapter.