As described in previous chapters many extracellular ligands such as neurotransmitters, hormones, cytokines, and sensory input rely upon G protein-coupled receptors (GPCRs) and linked signalling pathways to exert their actions at target cells. The established dogma is that these extracellular stimuli utilize a receptor, a heterotrimeric guanine nucleotide binding protein (G protein a^y subunit complex), and downstream effector proteins to transmit their signals across the plasma membrane (Hepler and Gilman 1992; Clapham and Neer 1997; Hamm 1998). Specifically, agonist occupancy of GPCRs causes exchange of GTP for GDP on Ga that activates Ga and stimulates its dissociation from the G^y complex. Free Ga-GTP and G^y then directly regulate the activity of well-defined effector proteins (e.g. adenylyl cyclases, phospholipases, ion channels) that, in the case of enzyme targets, generate second messenger molecules. In this model, second messengers activate signalling cascades that account for the many cellular actions initiated by the activated receptor. However, a wealth of new information highlights the limitations of this model and suggests that GPCRs utilize a growing list of additional protein binding partners to carry out their cellular actions (Bockaert and Pin 1999; Hall et al. 1999a). In some cases, these proteins regulate GPCR oligomerization, subcellular targeting, and pharmacology as well as the strength and duration of receptor-mediated signalling events. In other cases, these binding partners serve as previously unrecognized effectors or adaptors/scaffolds for other signalling proteins that propagate ligand-directed cellular signalling events independent of G proteins. This chapter focuses on the properties and cellular roles for these newly appreciated non-G protein binding partners of GPCRs.
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