Dopamine; Huntington Disease; Parkinson Disease; Protein Kinases; Psychiatry; Schizophrenia; Signal Transduction
Psychiatry: Connecticut Mental Health Center | Molecular Psychiatry, Division of | Neuroscience Research Training Program (NRTP) | Specialized Center of Research (SCOR) to Develop Gender-Sensitive Treatment for Tobacco Dependence | Stress & Addiction Clinical Research Program
Neuroscience Microarray Center, Yale
NIDA Neuroproteomics Center
Our research is focused on the molecular actions of dopamine in the striatum. Dopamine plays a key role in goal-directed behavior, as well as in reward and habit learning. The disruption of normal dopaminergic neurotransmission is known to underlie certain neuroodegenerative and neuropsychiatric diseases, including Huntington's and Parkinson's disease, and schizophrenia. Modulation of dopamine-regulated signaling pathways also plays an important role in the addictive actions of various drugs of abuse. Our studies of dopamine-dependent signal transduction in striatal neurons provide novel insights into how dopaminergic neurotransmission is altered in various diseases models and also provides a rational new approach to developing drugs that specifically affect these signaling pathways. An important component of our research is the development of biochemical methods to interrogate alterations in protein expression and regulation in specific neuronal cell types using novel proteomic approaches.
Specialized Terms: signal transduction; Structure and function of protein kinases and phosphatases
Extensive Research Description
Our 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.
cAMP-regulated signal transduction in striatal neurons.
Proteomics of specific neuronal populations.
Selective regulation of protein translation.
- Kurup et al. (2015) STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease. Proc. Natl. Acad. Sci. USA. 112:1202-7.
- Kitchen et al (2014) Decoding neuroproteomics: integrating the genome, translatome and functional anatomy. Nature Neuroscience. 17:1491-1499
- Carlyle et al. (2014) Age-Related Loss of Phosphodiesterase 4A Puts Association Cortex at Risk for Degeneration. Proc. Natl. Acad. Sci. USA. 111:5036 41.
- Wiseman et al (2013) Proteasomal degradation of eukaryotic elongation factor-2 kinase (EF2K) is regulated by cAMP-PKA signaling and the SCF[beta]TRCP ubiquitin E3 ligase. J. Biol. Chem. 288:17803-11
- 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.
- 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.