G protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors. The beta-arrestins, adaptor proteins involved in GPCR desensitization, may also act as scaffolds for signaling pathways such as the mitogen-activated protein kinase (MAPK) cascade. The MAPK family, which includes the extracellular-signal regulated kinases (ERK) 1 and 2, promotes cellular differentiation and proliferation. Herein, the activation of ERK1/2 upon stimulation of the GPCR bradykinin type 2 receptor (B2R) with bradykinin was examined. Various B2R mutants with modified C-termini were employed to examine the temporal kinetics of ERK1/2. One of these receptor mutants displayed a loss of beta-arrestin binding as well as greatly enhanced ERK1/2 activation, compared to the wild-type receptor, when a cluster of serine/threonine residues important for B2R internalization was mutated. The other receptor mutants exhibited a correlation between their affinity for beta-arrestin and the intensity of ERK1/2 activation. Data from a mouse embryonic fibroblast cell line null for beta-arrestin suggested that beta-arrestin is involved in late-phase ERK1/2 activation by the B2R. These data point to the involvement of beta-arrestin in the activation of the ERK1/2 MAPKs through the B2R.

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