β‐arrestin‐dependent Signaling of Dopamine D2 Receptor in the CNS: Opportunities for functionally selective therapeutic approaches.

In the brain, dopamine is implicated in the control of locomotion, cognition, emotion and affect as well as reward to drugs and natural stimuli. These effects are mediated by a subfamily of G protein‐coupled receptors (GPCR‐7TM). Based on the unexpected observation that mice lacking the β‐arrestin2 gene have markedly diminished locomotor responses to dopamine receptor stimulation, we showed that D2 dopamine receptors (D2R) mediated this effect through the ability of β‐arrestin2 to engage the Akt/GSK3 signaling pathway through the scaffolding of a signaling complex of β‐arrestin2/Akt/PP2A. A large body of evidence indicates that arrestins normally associated with desensitization of GPCRs can support G protein‐independent modes of signaling. Deregulation of the dopamine system has been suggested for certain symptoms of schizophrenia. Interestingly, antipsychotics that target many GPCRs are mixed partial/inverse agonists at D2R‐G protein activation, but are uniformly antagonists at β‐arrestin2‐D2R interactions. Genetic deletion of the downstream GSK3b gene in D2R, but not in D1R, expressing medium spiny neurons recapitulates loss of dopamine responsiveness. Thus, the functional selectivity of D2R signaling and the possibility to identify bias ligands for this pathway may provide new approaches for more selective therapies for CNS conditions associated with deregulation of the dopamine system.