Dopamine (DA) is a monoaminergic neurotransmitter that has been implicated in multiple neurological and psychiatric disorders in the CNS. The various actions of DA on target neurons are mediated via prototypical 7-transmembrane G protein-coupled receptors that couple to various effectors through G protein-dependent mechanisms. Our previous work has demonstrated that in the striatum, DA D2 receptors (D2R) mediate some of their actions through the Akt/GSK3 signaling pathway in a G protein-independent fashion via formation of a ?-arrestin 2/Akt/PP2A signaling complex leading to inhibition of Akt and the consequent activation of GSK3. Recent investigations in animals and humans have suggested an important role for the Akt/GSK3 signaling pathway in behavioral manifestations of elevated DA tone and in conditions like schizophrenia or mania. Clinically effective antipsychotic drugs that bind D2Rs show a high propensity to engage the ?-arrestin 2-mediated pathway, and the mood stabilizer lithium interferes with this pathway by inhibiting the stability of the ?-arrestin 2/Akt/PP2A signaling complex. Despite these exciting cellular results, the functional consequences of this pathway in vivo are poorly understood. The overall objective of this research is to generate a series of animal models in which the functioning of the pathway downstream of D2Rs can be precisely investigated at different levels downstream of ?-arrestin 2.
Aim 1 : We will examine the role of GSK3? and ?-catenin in the actions of DA by selectively manipulating them in postsynaptic D1R- and D2R-expressing neurons of the striatal efferent pathways.
Aim 2 : We will determine the contribution of ?-arrestin 2 by selectively inactivating and rescuing its function in the same postsynaptic neurons.
Aim 3 : Finally, we will engineer mouse lines that selectively express either wild type or D2Rs that can selectively couple through either a G protein- or a ?-arrestin 2-dependent mechanism in these same postsynaptic neurons. We anticipate that the biochemical, cell biological and behavioral analyses of these animal models will provide a unique understanding of how this novel D2R signaling mechanism transduces the actions of DA in striatum and that our results will provide novel insights into the development of new therapeutic agents.
The neurotransmitter dopamine has been implicated in multiple psychiatric disorders including Parkinson's and Huntington's diseases, schizophrenia, attention deficit-hyperactivity disorder, Tourette syndrome, mania, addiction and affective disorders. We have previously identified a novel signaling mechanism transduced through dopamine D2-like receptors. Since these receptors are primary targets for antipsychotic drugs, and because these drugs have wide application in psychiatry, this new signaling pathway may be important both in the etiology of these conditions and in their therapeutic management. The targeting of components in this pathway through generation of genetically-modified mice should clarify the in vivo role of this pathway under normal and pathophysiological actions of dopamine transmission and provide unique insights into the development of novel pharmacotherapies to treat the various psychiatric conditions.
|Pack, Thomas F; Orlen, Margo I; Ray, Caroline et al. (2018) The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation. J Biol Chem 293:6161-6171|
|Hultman, Rainbo; Ulrich, Kyle; Sachs, Benjamin D et al. (2018) Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability. Cell 173:166-180.e14|
|Rose, Samuel J; Pack, Thomas F; Peterson, Sean M et al. (2018) Engineered D2R Variants Reveal the Balanced and Biased Contributions of G-Protein and ?-Arrestin to Dopamine-Dependent Functions. Neuropsychopharmacology 43:1164-1173|
|Toth, Krisztian; Slosky, Lauren M; Pack, Thomas F et al. (2018) Ghrelin receptor antagonism of hyperlocomotion in cocaine-sensitized mice requires ?arrestin-2. Synapse 72:|
|Urs, Nikhil M; Peterson, Sean M; Caron, Marc G (2017) New Concepts in Dopamine D2 Receptor Biased Signaling and Implications for Schizophrenia Therapy. Biol Psychiatry 81:78-85|
|Zhu, Lu; Rossi, Mario; Cui, Yinghong et al. (2017) Hepatic ?-arrestin 2 is essential for maintaining euglycemia. J Clin Invest 127:2941-2945|
|Zhu, Lu; Almaça, Joana; Dadi, Prasanna K et al. (2017) ?-arrestin-2 is an essential regulator of pancreatic ?-cell function under physiological and pathophysiological conditions. Nat Commun 8:14295|
|Urs, Nikhil M; Gee, Steven M; Pack, Thomas F et al. (2016) Distinct cortical and striatal actions of a ?-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proc Natl Acad Sci U S A 113:E8178-E8186|
|Hultman, Rainbo; Mague, Stephen D; Li, Qiang et al. (2016) Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology. Neuron 91:439-52|
|Peterson, Sean M; Pack, Thomas F; Wilkins, Angela D et al. (2015) Elucidation of G-protein and ?-arrestin functional selectivity at the dopamine D2 receptor. Proc Natl Acad Sci U S A 112:7097-102|
Showing the most recent 10 out of 42 publications