TY - JOUR
T1 - Acute phencyclidine treatment induces extensive and distinct protein phosphorylation in rat frontal cortex
AU - Palmowski, Pawel
AU - Rogowska-Wrzesinska, Adelina
AU - Williamson, James
AU - Beck, Hans C
AU - Mikkelsen, Jens D
AU - Hansen, Henrik H
AU - Jensen, Ole N
PY - 2014/3/7
Y1 - 2014/3/7
N2 - 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.
AB - 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.
KW - Amino Acid Sequence
KW - Animals
KW - Calcium/metabolism
KW - Disease Models, Animal
KW - Energy Metabolism/drug effects
KW - Hallucinogens/adverse effects
KW - Homeostasis/drug effects
KW - Humans
KW - Male
KW - Molecular Sequence Data
KW - Nerve Tissue Proteins/analysis
KW - Phencyclidine/adverse effects
KW - Phosphopeptides/analysis
KW - Phosphorylation
KW - Prefrontal Cortex/chemistry
KW - Protein Processing, Post-Translational
KW - Rats
KW - Rats, Wistar
KW - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
KW - Schizophrenia/chemically induced
KW - Synaptic Transmission/drug effects
U2 - 10.1021/pr4010794
DO - 10.1021/pr4010794
M3 - Journal article
C2 - 24564430
SN - 1535-3893
VL - 13
SP - 1578
EP - 1592
JO - Journal of Proteome Research
JF - Journal of Proteome Research
IS - 3
ER -