A Tale of Two Sites – How ubiquitination of a G protein-coupled receptor is coupled to its lysosomal trafficking from distinct receptor domains

Abstract

The β₂-adrenergic receptor (β₂AR) is a prototypical Gs-coupled receptor belonging to the superfamily of seven transmembrane spanning heptahelical receptors (7TMRs, or G protein-coupled receptors [GPCRs])—therapeutically the most diverse and accessible class of cell surface receptors. The classic pathway of β₂AR signalling (Fig. 1) is triggered by activation of the heterotrimeric G protein G_s by agonists (catecholamines - noradrenaline and adrenaline). This in turn activates adenylyl cyclase leading to the generation of second messenger signaling molecules (cyclic adenosine monophosphates, cAMP) which subsequently activate protein kinase A (PKA) as well as some ion channels, such as the class C type of L-type calcium channels, CaV1.2. ³¹ Here in we review how β₂AR trafficking and signalling is regulated by the post-translational modification, ubiquitination.¹

Figures and Tables

Figure 1 (A) According to the classic GPCR signal ing paradigm, upon agonist binding the β2AR is activated leading to heterotrimeric G protein coupling to the β2AR, dissociation of the Gα from the βγ-subunits and subsequent signaling downstream. Following receptor activation, the agonist-bound β2AR is phosphorylated on its carboxyl tail (CT) by G protein-coupled receptor kinases (GRKs) leading to recruitment of β-arrestins and short-term desensitization of the β2AR. Consequently, β-arrestins also manifest in a second round of extended signaling (independent of G proteins) leading to the prolonged agonist-induced effect as observed in several receptor systems. (B) In addition, the GRK-phosphorylated and β-arrestin scaffolded β2AR is ubiquitinated at lysine residues on two distinct receptor domains: intracellular loop 3 (L3) and the carboxyl tail (CT), which signals the β2AR to lysosomal degradation. The global reduction in cellular receptor levels thus characterizes and provides an explanation for the long-term desensitization of GPCRs upon prolonged agonist-stimulation.