Dopamine (DA) is a monoaminergic neurotransmitter that has been implicated in multiple disorders such as Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder, Tourette syndrome, addiction and affective disorders. At the cellular level the various actions of DA on target neurons are mediated via a family of 5 distinct G protein-coupled receptors. The D1-like (D1 and D5) receptors are mostly coupled to activation of the cAMP signaling cascade through the G protein Gs whereas the D2-like receptors (D2, D3 and D4) signal through Gi/Go and can inhibit the cAMP cascade. D2-like receptors also modulate Ca2+ and K + channels and can engage other signals such as MAP kinase pathways. Whereas most classical animal and cellular studies have focused on cAMP mediating the actions of DA, the applicability or potential contribution of other signaling pathways is still not fully understood. Recent investigations in mice have revealed that behavioral manifestations of elevated DA tone in the brain in response to genetic or pharmacological manipulations and the ability of lithium to antagonize these behaviors correlate with modulation of the Akt/GSK-3 signaling pathway in a cAMP-independent fashion. The overall objective of the proposed research is to define the molecular and cellular mechanisms that contribute to these processes with the goal of better understanding physiological and pathological conditions. Studies will be conducted both in cellular systems as well as in normal and genetically modified animal models.
Aim 1 : We will attempt to characterize the mechanisms by which dopamine regulate Akt/GSK-3 signaling. This will include determining which of the DA receptors and molecular signaling intermediates engage the Akt pathway and reconstitution of those interactions in cellular systems.
Aim 2 : We will address characterization of the molecular targets of GSK-3 that mediate responses to DA.
Aim 3 : These proposed experiments will examine the role of Akt/GSK-3 in DA-associated behaviors, such as those modeling affective and psychotic disorders, in animals carrying tissue-specific genetic deletion of various GSK-3 isoforms. Results from these studies should broaden our understanding of the cellular and molecular mechanisms mediating the actions of DA in normal and pathophysiological conditions and provide insight into potential novel therapeutic approaches for various psychiatric conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH073853-02
Application #
7067203
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Winsky, Lois M
Project Start
2005-05-17
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
2
Fiscal Year
2006
Total Cost
$421,866
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Marion, Sébastien; Urs, Nikhil M; Peterson, Sean M et al. (2014) Dopamine D2 receptor relies upon PPM/PP2C protein phosphatases to dephosphorylate huntingtin protein. J Biol Chem 289:11715-24
Wang, Chong; Wu, Huixian; Evron, Tama et al. (2014) Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat Commun 5:4355
Urs, N M; Caron, M G (2014) The physiological relevance of functional selectivity in dopamine signalling. Int J Obes Suppl 4:S5-8
Daigle, Tanya L; Ferris, Mark J; Gainetdinov, Raul R et al. (2014) Selective deletion of GRK2 alters psychostimulant-induced behaviors and dopamine neurotransmission. Neuropsychopharmacology 39:2450-62
Burkhalter, Martin D; Fralish, Gregory B; Premont, Richard T et al. (2013) Grk5l controls heart development by limiting mTOR signaling during symmetry breaking. Cell Rep 4:625-32
Gregory, K J; Herman, E J; Ramsey, A J et al. (2013) N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement. J Pharmacol Exp Ther 347:438-57
Philipp, Melanie; Evron, Tama; Caron, Marc G (2013) The role of arrestins in development. Prog Mol Biol Transl Sci 118:225-42
Barak, Larry S; Peterson, Sean (2012) Modeling of bias for the analysis of receptor signaling in biochemical systems. Biochemistry 51:1114-25
Daigle, Tanya L; Caron, Marc G (2012) Elimination of GRK2 from cholinergic neurons reduces behavioral sensitivity to muscarinic receptor activation. J Neurosci 32:11461-6
Urs, Nikhil M; Snyder, Joshua C; Jacobsen, Jacob P R et al. (2012) Deletion of GSK3? in D2R-expressing neurons reveals distinct roles for ?-arrestin signaling in antipsychotic and lithium action. Proc Natl Acad Sci U S A 109:20732-7

Showing the most recent 10 out of 30 publications