Phosphoproteomic analysis reveals compensatory effects in the piriform cortex of VX nerve agent exposed rats.
To gain insights into the toxicity induced by the nerve agent VX, an MS-based phosphoproteomic analysis was carried out on the piriform cortex region of brains from VX-treated rats. Using isobaric tag based TMT labeling followed by titanium dioxide enrichment strategy, we identified 9975 unique phosphosites derived from 3287 phosphoproteins. Temporal changes in the phosphorylation status of peptides were observed over a time period of 24 h in rats exposed to a 1× LD50, intravenous (i.v.) dose with the most notable changes occurring at the 1 h postexposure time point. Five major functional classes of proteins exhibited changes in their phosphorylation status: (i) ion channels/transporters, including ATPases, (ii) kinases/phosphatases, (iii) GTPases, (iv) structural proteins, and (v) transcriptional regulatory proteins. This study is the first quantitative phosphoproteomic analysis of VX toxicity in the brain. Understanding the toxicity and compensatory signaling mechanisms will improve the understanding of the complex toxicity of VX in the brain and aid in the elucidation of novel molecular targets that would be important for development of improved countermeasures. All MS data have been deposited in the ProteomeXchange with identifier PXD001184 (http://proteomecentral.proteomexchange.org/dataset/PXD001184).
Institute of Bioinformatics, International Tech Park, Bangalore, India; School of Life Sciences, Centre for Bioinformatics, Pondicherry University, Puducherry, India; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Raja Sekhar
RS
Nirujogi
James D
JD
Wright
Srikanth S
SS
Manda
Jun
J
Zhong
Chan Hyun
CH
Na
James
J
Meyerhoff
Bernard
B
Benton
Rabih
R
Jabbour
Kristen
K
Willis
Min-Sik
MS
Kim
Akhilesh
A
Pandey
Jennifer W
JW
Sekowski
D000595:Amino Acid Sequence; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D008297:Male; D008969:Molecular Sequence Data; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D010748:Phosphopeptides / Q000032:analysis / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D066195:Piriform Cortex / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D020543:Proteome / Q000737:chemistry / Q000378:metabolism*; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
D002619:Chemical Warfare Agents; D009946:Organothiophosphorus Compounds; D010748:Phosphopeptides; D010750:Phosphoproteins; D020543:Proteome; C009680:VX-agent
Animal proteomics; Phosphoproteomics; Piriform cortex; Signal transduction; VX