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NIDA Proteomics Center
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Investigators
> Angus Nairn
Regulation of Synaptic Structure
and Function by Drugs of Abuse
Angus Nairn, Department of Psychiatry, Pharmacology, CNNR,
Yale University The behavioral
adaptations that accompany drug addiction are believed to result from both short
and long-term adaptive molecular changes in brain reward centers. Moreover it is
likely that exposure to drugs of abuse regulates intracellular signaling
processes which in turn leads to alteration of gene expression, protein
translation and post-translational modifications of proteins. As a result,
repeated exposure to drugs of abuse leads to long-term, stable alterations in
neuronal signaling systems that are critical for the changes in brain chemistry
and structure of the addicted brain. Many studies of the effects of drugs of
abuse have focused on the phosphorylation of proteins involved in glutamatergic
and dopaminergic pathways, since these two neurotransmitter pathways converge in
regions of the brain involved in the rewarding and cognitive effects of
psychostimulants, such as the prefrontal cortex, the dorsal, and ventral
striatum. As a result, much of our previous work, carried out as a long-term
collaboration with Center member Paul Greengard, has focused on the regulation
of protein phosphorylation by dopamine and glutamate in the dorsal and ventral
striatum. Many of these studies have involved regulation of the serine/threonine
phosphatases, PP1. Through the regulation of DARPP-32, PP1 plays a critical role
in mediating the effects of drugs of abuse. Other studies have shown that PP1 is
recruited to dendritic spines via an interaction with spinophilin and its
homolog, neurabin, where PP1 can then dephosphorylate spine-enriched proteins,
such as neurotransmitter receptors.
Several of our ongoing studies have benefited from the use of the proteomic
resources and support of the NIDA Neuroprotomics Center. In future studies, we
propose to (1) use protein profiling methods to study the effect of cocaine
exposure on the proteins associated with the post-synaptic density; (2) study
the phosphorylation and function of the Rho-GEF, LFC, which we have found to
play a role in regulating the actin cytoskeleton in spines; (3) further
characterize a family of substrates for protein kinase A that are enriched in
striatal medium spiny neurons; (4) use both protein profiling and
phosphoproteomic analysis to identify phosphoprotein substrates that are
differentially regulated by PP1 isoforms. |
