b-arrestins play a vital role in the promotion of the formation of multi-protein signaling complexes with ERK and various tyrosine kinases involved in these mitogenic pathways independent of G protein activation. Specific GRKs can induce receptor phosphorylation that can lead to agonist-stimulated ERK activation in the absence of G protein activation. The angiotensin II activation of angiotensin II type 1 receptor (AT1R) with a mutation in the conserved DRY motif (at the intracellular end of TM3) doesn’t cause any G protein-mediated signaling, but maintains b-arrestin recruitment and ERK activation.74,75 In addition, the use of siRNA against b-arrestin 2 blocks the angiotensinstimulated ERK activation.76 This elucidates that GPCRs can signal exclusively through b-arrestins even in the absence of G protein coupling. This appears to be a more general feature of GPCR signaling as the same has been shown for another rhodopsin family receptor b2AR77 and also for a secretin family receptor type 1 PTH/PTH-related peptide receptor.78 A general view of this biased signaling is shown in Figure 11.15, where either a ligand could bias the receptor towards b-arrestin pathway, or a protein might be innately biased towards b-arrestin pathway as shown recently for the CXCR7 receptor.79

11.3.2.4GPCR Dimers and Interaction with Other Proteins

All prior discussion in the chapter implicitly assumed that GPCRs couple to G proteins as monomers. Any functional association of a GPCR with its copy, or a di erent GPCR, or another protein only increases the GPCR repertoire of signaling mechanisms for selective functional control within the cell. Early evidence of GPCR dimerization was observed in recombinant cell systems that over-expressed these receptors, which raised doubts about their functional significance.80 There is now strong functional evidence based on experiments

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Figure 11.15 Balanced and biased signaling by GPCRs. Reproduced with permission from Rajagopal et al., Proc. Nat. Acad. Sci. U. S. A., 107(2), 628. Copyright 2010.