ABSTRACT
The arrestins constitute a family of proteins that are capable of interacting with G-protein-coupled receptors (GPCRs) after their activation by agonists and subsequent phosphorylation by GPCR kinase (GRKs) (Stephen and Lefkowitz 2002). Arrestins recognize both GRK phosphorylation sites on the receptor and the active conformation of the receptor after agonist binding, which together drive robust arrestin association with the receptors (Luttrell and Lefkowitz 2002). Arrestin binding leads to uncoupling of the receptor from its cognate G protein in such a way that despite the continued activation of the receptor by the agonist, it cannot exchange the guanosine triphosphate group on the G-protein α subunit for guanosine diphosphate (Gainetdinov et al. 2004), eventually causing desensitization of G-protein signaling via downstream second messenger molecules (Stephen and Lefkowitz 2002; Gainetdinov et al. 2004; Lohse et al. 1990; Lefkowitz 2004) (Figure 18.1). Although most of the research regarding the desensitization process has been carried out using the β2-adrenoceptor as a model, it is now clear that this process regulates the function of many GPCRs,
18.1 Introduction: Arrestins ......................................................................................................... 371 18.1.1 β-Arrestins: Mood Disorders and Antidepressants .................................................. 372 18.1.2 β-Arrestin Ubiquitination: Depressive Disorder and Antidepressants ..................... 373 18.1.3 Protein Kinase B, Glycogen Synthase Kinase-3, β-Arrestin-2, Lithium, and
Antidepressants ......................................................................................................... 374 18.2 Mitogen-Activated Protein Kinases ...................................................................................... 375
18.2.1 ERK: Scaffolding Roles of β-Arrestins .................................................................... 376 18.2.1.1 ERK: Depression and Antidepressants ...................................................... 376
18.2.2 JNK: Scaffolding Roles of β-Arrestins..................................................................... 377 18.2.2.1 JNK: Depression and Antidepressants ...................................................... 377
18.2.3 p38: Scaffolding Roles of β-Arrestins ...................................................................... 378 18.2.3.1 p38: Depression and Antidepressants ........................................................ 378
18.3 β-Arrestin Regulation of Transcription and Antidepressants ............................................... 379 18.3.1 Inhibitor of Nuclear Factor κBα................................................................................ 379 18.3.2 Transcription Factors: CREB, c-fos, and p27 ...........................................................380
