Arrestins: Role in the Desensitization, Sequestration, and Vesicular Trafficking of G Protein-Coupled Receptors - Progress in Molecular Biology and Translational Science - page 92

have been agonist activated. There is no evidence that second messenger-
dependent protein kinase phosphorylation-dependent uncoupling of
GPCRs from heterotrimeric G proteins requires the association of b -arrestin
with GPCRs. 3 In contrast, phosphorylation by GRKs (homologous desen-
sitization) occurs only following the agonist-dependent isomerization of
GPCRs to an activated state that results in GRK-mediated phosphorylation
of distinct serine and threonine residues within intracellular GPCR
domains. 18 Specifically, GRKs phosphorylate agonist-activated GPCRs
because the activated receptor itself activates the kinase. 19 The GRK family
consists of seven members (GRK1-7) that display different distribution pat-
terns and show receptor-specific preferences. 20-22 Whereas GRK1 and 7
expression is restricted to retinal rods and cones and GRK4 displays limited
expression in the kidneys, testis, and cerebellum, GRK2, -3, -5, and -6 are
ubiquitously expressed in mammalian tissues. 22,23 However, GRK-
mediated phosphorylation is not sufficient to cause desensitization of most
GPCRs, but rather requires the recruitment of the cytosolic cofactor protein
arrestin. b -Arrestins bind to agonist-activated and phosphorylated GPCRs
and serve to sterically uncouple receptors from heterotrimeric G proteins
resulting in the termination of G protein-dependent signal transduc-

tion 10,11,24

( Fig. 4.1 ). Accordingly, the first function of b -arrestins is to

Figure 4.1 Classical model of G protein-coupled receptor kinase (GRK)-mediated
G protein-coupled receptor (GPCR) desensitization. Agonist binding leads to conforma-
tional changes allowing for coupling and activation of heterotrimeric G proteins. This
leads to the specific phosphorylation of agonist-activated receptors by GRKs at various
intracellular domains, primarily intracellular loop three and the carboxyl terminus. Sub-
sequently, arrestin is recruited to the phosphorylated receptor, where it sterically
uncouples the receptor from its cognate G protein and, in turn, leads to receptor desen-
sitization. A, agonist; G, G protein; GRK, G protein-coupled receptor kinase; P, phosphate
moiety; b-ARR, b-arrestin.