Acute Phencyclidine Treatment Induces Extensive and Distinct Protein Phosphorylation in Rat Frontal Cortex

• Published in: Journal of proteome research Vol. 13; no. 3; pp. 1578 - 1592
• Main Authors: Palmowski, Pawel, Rogowska-Wrzesinska, Adelina, Williamson, James, Beck, Hans C, Mikkelsen, Jens D, Hansen, Henrik H, Jensen, Ole N
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 07.03.2014
• Subjects: Amino Acid Sequence; Animals; Calcium - metabolism; Disease Models, Animal; Energy Metabolism - drug effects; Hallucinogens - adverse effects; Homeostasis - drug effects; Humans; Male; Molecular Sequence Data; Nerve Tissue Proteins - analysis; Nerve Tissue Proteins - metabolism; Phencyclidine - adverse effects; Phosphopeptides - analysis; Phosphorylation; Prefrontal Cortex - chemistry; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; Protein Processing, Post-Translational; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Schizophrenia - chemically induced; Schizophrenia - metabolism; Schizophrenia - pathology; Synaptic Transmission - drug effects; phencyclidine; proteomics; rat; LC–MS; schizophrenia; PCP; phosphorylation
• ISSN: 1535-3893; 1535-3907
• DOI: 10.1021/pr4010794

Phencyclidine (PCP), a noncompetitive N-methyl-d-aspartate receptor antagonist, induces psychotomimetic effects in humans and animals. Administration of PCP to rodents is used as a preclinical model for schizophrenia; however, the molecular mechanisms underlying the symptoms remain largely unknown. Acute PCP treatment rapidly induces behavioral and cognitive deficits; therefore, post-translational regulation of protein activity is expected to play a role at early time points. We performed mass-spectrometry-driven quantitative analysis of rat frontal cortex 15, 30, or 240 min after the administration of PCP (10 mg/kg). We identified and quantified 23 548 peptides, including 4749 phosphopeptides, corresponding to 2604 proteins. A total of 352 proteins exhibited altered phosphorylation levels, indicating that protein phosphorylation is involved in the acute response to PCP. Computational assessment of the regulated proteins biological function revealed that PCP perturbs key processes in the frontal cortex including calcium homeostasis, organization of cytoskeleton, endo/exocytosis, and energy metabolism. This study on acute PCP treatment provides the largest proteomics and phosphoproteomics data sets to date of a preclinical model of schizophrenia. Our findings contribute to the understanding of alterations in glutamatergic neurotransmission in schizophrenia and provide a foundation for discovery of novel targets for pharmacological intervention.