ABSTRACT
G-protein-coupled receptors (GPCRs) continue to be a primary target for novel drug discovery [1,2]. They comprise seven trans-membrane-spanning helices linked by intracellular and extracellular loops with an extracellular
N
-terminus and an intracellular
C-
terminus [3]. Agonist stimulation of GPCRs activates a range of second messenger pathways via the family of heterotrimeric G-proteins. The agonist-mediated response usually decreases rapidly via a process known as desensitization and often involves GPCRs becoming phosphorylated by G-protein receptor kinases [4]. This allows the binding of an arrestin protein, leading to uncoupling of the GPCRs from their G-proteins and resulting in attenuation of second messenger signaling [5]. Agonist-mediated activation also promotes a rapid sequestration of GPCRs away from the plasma membrane into the endosomal pathway, from where they are sorted either into acidic perinuclear recycling endosomes or into lysosomes for proteolysis (Figure 30.1). Other cell surface-expressed receptors such as tyrosine kinases also internalize into the endosomal pathway after activation, where they are then sorted for recycling or future degradation [6].
