Neuroscience Microarray Center, Yale
NIDA Neuroproteomics Center
Our research is focused on the molecular actions of dopamine in the basal ganglia. The disruption of normal dopaminergic neurotransmission is known to underlie certain neurological diseases, including Huntington's and Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder. Modulation of dopamine-regulated signaling pathways is also likely to play an important role in the addictive actions of various drugs of abuse. Our studies of basal ganglia phosphoproteins will hopefully provide insights into how dopaminergic neurotransmission is altered in various diseases models and also to provide a rational new approach to developing drugs that specifically affect these phosphoproteins or their targets.
Extensive Research DescriptionOur discovery and characterization of striatal phosphoproteins controlled by dopamine, including DARPP-32, RCS, and ARPP-16, provides a rational approach to the elucidation of the molecular actions of dopamine. Our current studies focus on the biochemical characterization of DARPP-32 and its target, protein phosphatase-1, on RCS and the regulation of calmodulin-dependent signaling, and on ARPP-16 and its potential involvement in regulation of protein phosphatase 2A. In these studies we utilize we use biochemical, molecular, and cell biological methods to characterize the role of these proteins in signal transduction pathways in striatal neurons. In addition, we use mouse models where striatal phosphoproteins and their targets have been “knocked out” to investigate the functions of these dopamine-regulated pathways in a variety of behavioral paradigms. Other interests of the laboratory include the signaling processes that regulate the F-actin cytoskeleton in dendritic spines.
cAMP-regulated signal transduction in striatal neurons.
Proteomics of specific neuronal populations.
Selective regulation of protein translation.
- Craft, et al (2013) Recent advances in quantitative neuroproteomics. Methods. 61(3):186-218.
- Walaas, et al. (2011) Beyond the Dopamine Receptor: Regulation and Roles of Serine/Threonine Protein Phosphatases. Front Neuroanat. 5:50.
- Krueger, et al (2009) Effects of chronic cocaine administration on cognitive function in C57BL/6 mice. Behavioral Pharmacology. 20:695-704.
- McAvoy, et al (2009) Phosphorylation of RapGAP1, a striatally enriched protein, by protein kinase A controls Rap activity and dendritic spine morphology. Proc. Natl. Acad. Sci. USA. 106:3531-3536.
- Stipanovich, et al (2008) A phosphatase cascade by which natural rewards and drugs of abuse regulate nucleosomal response. Nature 453:879-884.
- Ahn, et al (2007) Protein kinase A activates Protein Phosphatase 2A by phosphorylation of the B56 subunit. Proc. Natl. Acad. Sci. USA. 104:2979-84.