The basal ganglia is a critical regulator of a myriad of processes in the brain including motor control and behavior. This system is divided into several nuclei based upon anatomical location and connectivity, the largest of which is referred to as the striatum. The predominant neuronal cell type of the striatum is the inhibitory medium spiny neuron (MSN), which form the direct and indirect pathway based upon functional differences in anatomy and biochemistry. Biochemically, both MSN populations are innervated by dopaminergic neurons from the midbrain and respond to the monoamine neurotransmitter dopamine. However, dopamine signals through two families of G-protein coupled receptors (GPCR)s referred to as D1 and D2 GPCRs, which are selectively expressed in MSNs of the direct or indirect pathway, respectively. D1 and D2 GPCRs can be further distinguished biochemically by their respective positive or negative coupling to the generation of the downstream second messenger cAMP. Perturbations to dopamine signal transduction are implicated in a number of mental health disorders including anxiety, schizophrenia, depression, and attention deficit hyperactivity disorder. Given the prevalence of these disorders world-wide, studies to elucidate the basic signal transduction mechanisms responsible for dopamine signal transduction are necessary to develop more effective strategies of pharmacological intervention. Recent work has identified a G-protein independent modality of dopamine signaling that regulates behavior. This pathway is dependent upon 2-arrestin-2 mediated complex formation of AKT, GSK-32, and protein phosphatase 2 (PP2A). Dopamine stimulus promotes formation of this complex, resulting in activation of GSK-32 through inhibition of AKT by PP2A, and activation of dopamine dependent behavior. Currently, downstream targets of GSK-32 in this signaling paradigm have not been identified. The exciting finding that clinically effective antipsychotics target 2-arrestin- 2 mediated dopamine signaling provides further justification for delineating the downstream effectors of this pathway. Given the role for 2-catenin as a primary target of GSK-32 action and numerous reports suggesting that 2-catenin may be a downstream effector molecule necessary for the efficacy of psychotropic drugs we propose to test the hypothesis that that dopamine signaling and the actions of psychotropic drugs are mediated in part by 2-catenin. This hypothesis will be tested by interrogation of two specific aims that utilize a comprehensive genetic analysis to: 1) Characterize 2-catenin signaling in mouse models of hyper- dopaminergia and hypo-dopaminergia and 2) Determine the necessity for 2-catenin signaling in mediating dopamine dependent signaling and the actions of psychotropic drugs using floxed alleles of 2-catenin, which attenuate or potentiate 2-catenin signaling. Completion of this proposal will provide further insight into dopamine dependent signaling and behaviors. Ultimately, this may provide a framework for the development of more efficacious treatments of neurological disease.
This research proposal will provide new insight into the mechanism of dopamine signal transduction. Anticipated manuscripts from this study will describe novel pathways that can be targeted for pharmacological intervention in neurological disease. Future studies based upon this work will improve the quality of life for those affected by disease and decrease the financial burden for patient care.
|Snyder, Joshua C; Rochelle, Lauren K; Barak, Larry S et al. (2013) The stem cell-expressed receptor Lgr5 possesses canonical and functionally active molecular determinants critical to Î²-arrestin-2 recruitment. PLoS One 8:e84476|
|Barak, Larry S; Bai, Yushi; Snyder, Joshua C et al. (2013) Triphenylmethane dye activation of beta-arrestin. Biochemistry 52:5403-14|
|Urs, Nikhil M; Snyder, Joshua C; Jacobsen, Jacob P R et al. (2012) Deletion of GSK3Î² in D2R-expressing neurons reveals distinct roles for Î²-arrestin signaling in antipsychotic and lithium action. Proc Natl Acad Sci U S A 109:20732-7|