Beta-arrestin mediates desensitization and internalization of beta-adrenergic 
receptors (betaARs), but also acts as a scaffold protein in extracellular 
signal-regulated kinase (ERK) cascade. Thus, we have examined the role of 
beta-arrestin2 in the betaAR-mediated ERK signaling pathways. Isoproterenol 
stimulation equally activated cytoplasmic and nuclear ERK in COS-7 cells 
expressing beta1AR or beta2AR. However, the activity of nuclear ERK was enhanced 
by co-expression of beta-arrestin2 in beta2AR-but not beta1AR-expressing cells. 
Pertussis toxin treatment and blockade of Gbetagamma action inhibited 
beta-arrestin2-enhanced nuclear activation of ERK, suggesting that 
beta-arrestin2 promotes nuclear ERK localization in a Gbetagamma dependent 
mechanism upon receptor stimulation. beta2AR containing the carboxyl terminal 
region of beta1AR lost the beta-arrestin2-promoted nuclear translocation. As the 
carboxyl terminal region is important for beta-arrestin binding, these results 
demonstrate that recruitment of beta-arrestin2 to carboxyl terminal region of 
beta2AR is important for ERK localization to the nucleus.