title: Chronic morphine alters the presynaptic protein profile: identification of novel molecular targets using proteomics and network analysis.
abstract: Opiates produce significant and persistent changes in synaptic transmission; knowledge of the proteins involved in these changes may help to understand the molecular mechanisms underlying opiate dependence. Using an integrated quantitative proteomics and systems biology approach, we explored changes in the presynaptic protein profile following a paradigm of chronic morphine administration that leads to the development of dependence. For this, we isolated presynaptic fractions from the striata of rats treated with saline or escalating doses of morphine, and analyzed the proteins in these fractions using differential isotopic labeling. We identified 30 proteins that were significantly altered by morphine and integrated them into a protein-protein interaction (PPI) network representing potential morphine-regulated protein complexes. Graph theory-based analysis of this network revealed clusters of densely connected and functionally related morphine-regulated clusters of proteins. One of the clusters contained molecular chaperones thought to be involved in regulation of neurotransmission. Within this cluster, cysteine-string protein (CSP) and the heat shock protein Hsc70 were downregulated by morphine. Interestingly, Hsp90, a heat shock protein that normally interacts with CSP and Hsc70, was upregulated by morphine. Moreover, treatment with the selective Hsp90 inhibitor, geldanamycin, decreased the somatic signs of naloxone-precipitated morphine withdrawal, suggesting that Hsp90 upregulation at the presynapse plays a role in the expression of morphine dependence. Thus, integration of proteomics, network analysis, and behavioral studies has provided a greater understanding of morphine-induced alterations in synaptic composition, and identified a potential novel therapeutic target for opiate dependence.
authors: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, United States of America.
authors: Noura S
authors: NS
authors: Abul-Husn
authors: Suresh P
authors: SP
authors: Annangudi
authors: Avi
authors: A
authors: Ma'ayan
authors: Dinah L
authors: DL
authors: Ramos-Ortolaza
authors: Steven D
authors: SD
authors: Stockton
authors: Ivone
authors: I
authors: Gomes
authors: Jonathan V
authors: JV
authors: Sweedler
authors: Lakshmi A
authors: LA
authors: Devi
mesh_terms: D000818:Animals; D002908:Chronic Disease; D016000:Cluster Analysis; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009021:Morphine Dependence / Q000378:metabolism; D017729:Presynaptic Terminals / Q000737:chemistry*; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000032:analysis; D040901:Proteomics / Q000379:methods; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D011506:Proteins; C088460:cysteine string protein; D009020:Morphine