Ahmed, M. R.; Dunning, J. L.; Zheng, C.; Kim, S.; Milanes, S.; Bozorgmehr, C.; Janzen-Meza, J.; Yao, K.; Li, H.; Gurevich, V. V.; Gurevich, E. V.

Arrestins play key role in desensitization of G protein-coupled receptors. Direct signaling role of arrestins has also been documented. Two ubiquitously expressed arrestin isoforms, arrestin-2 and -3 (Arr3), perform similarly in receptor desensitization and share many signaling functions, enabling them to substitute for one another. However, certain signaling roles are specific to each isoform. Mice lacking Arr3 (A3KO) show blunted acute responsiveness to the locomotor stimulatory effect of amphetamine (AMPH). Here we demonstrate that AMPH- and cocaine-induced locomotion of A3KO mice is significantly reduced. This loss-of-function phenotype suggests that Arr3-mediated signaling contributes to the effect. Virus-driven expression of Arr3 in caudate-putamen of A3KO and wild type mice suppressed AMPH-induced locomotion. In contrast, restoration of Arr3 in nucleus accumbens rescued locomotor response. Thus, in caudate-putamen Arr3 participates in the desensitization of dopamine receptors, whereas Arr3-dependent signaling in nucleus accumbens underlies the molecular mechanism of the locomotor response and sensitization. Using monofunctional Arr3-derived peptides, we showed that in the nucleus accumbens Arr3 promoted drug-induced locomotor responses via facilitation of JNK3 activation.