AKAP signaling in reinstated cocaine seeking revealed by iTRAQ proteomic analysis.

Reissner KJ, Uys JD, Schwacke JH, Comte-Walters S, Rutherford-Bethard JL, Dunn TE, Blumer JB, Schey KL, Kalivas PW
J Neurosci. 2011 31 (15): 5648-58

PMID: 21490206 · PMCID: PMC3595532 · DOI:10.1523/JNEUROSCI.3452-10.2011

To identify candidate proteins in the nucleus accumbens (NAc) as potential pharmacotherapeutic targets for treating cocaine addition, an 8-plex iTRAQ (isobaric tag for relative and absolute quantitation) proteomic screen was performed using NAc tissue obtained from rats trained to self-administer cocaine followed by extinction training. Compared with yoked-saline controls, 42 proteins in a postsynaptic density (PSD)-enriched subfraction of the NAc from cocaine-trained animals were identified as significantly changed. Among proteins of interest whose levels were identified as increased was AKAP79/150, the rat ortholog of human AKAP5, a PSD scaffolding protein that localizes signaling molecules to the synapse. Functional downregulation of AKAP79/150 by microinjecting a cell-permeable synthetic AKAP (A-kinase anchor protein) peptide into the NAc to disrupt AKAP-dependent signaling revealed that inhibition of AKAP signaling impaired the reinstatement of cocaine seeking. Reinstatement of cocaine seeking is thought to require upregulated surface expression of AMPA glutamate receptors, and the inhibitory AKAP peptide reduced the PSD content of protein kinase A (PKA) as well as surface expression of GluR1 in NAc. However, reduced surface expression was not associated with changes in PKA phosphorylation of GluR1. This series of experiments demonstrates that proteomic analysis provides a useful tool for identifying proteins that can regulate cocaine relapse and that AKAP proteins may contribute to relapse vulnerability by promoting increased surface expression of AMPA receptors in the NAc.

MeSH Terms (23)

A Kinase Anchor Proteins Amino Acid Sequence Animals Behavior, Animal Blotting, Western Chromatography, High Pressure Liquid Chromatography, Ion Exchange Cocaine-Related Disorders Cyclic AMP-Dependent Protein Kinases Male Molecular Sequence Data Nerve Tissue Proteins Neural Networks (Computer) Nucleus Accumbens Proteomics Rats Rats, Sprague-Dawley Receptors, AMPA Self Administration Signal Transduction Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Subcellular Fractions Synapses

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