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Parthasarathy R.N.,Behavioral Science and Research Services | Parthasarathy R.N.,University of Louisville | Lakshmanan J.,Behavioral Science and Research Services | Lakshmanan J.,University of Louisville | And 11 more authors.
Molecular and Cellular Biochemistry | Year: 2013

The therapeutic effects of lithium in bipolar disorder are poorly understood. Lithium decreases free inositol levels by inhibiting inositol monophosphatase 1 and myoinositol 3-phosphate synthase (IPS). In this study, we demonstrate for the first time that IPS can be phosphorylated. This was evident when purified rat IPS was dephosphorylated by lambda protein phosphatase and analyzed by phospho-specific ProQ-Diamond staining and Western blot analysis. These techniques demonstrated a mobility shift consistent with IPS being phosphorylated. Mass spectral analysis revealed that Serine-524 (S524), which resides in the hinge region derived from exon 11 of the gene, is the site for phosphorylation. Further, an antibody generated against a synthetic peptide of IPS containing monophosphorylated-S524, was able to discriminate the phosphorylated and non-phosphorylated forms of IPS. The phosphoprotein is found in the brain and testis, but not in the intestine. The intestinal IPS isoform lacks the peptide bearing S524, and hence, cannot be phosphorylated. Evidences suggest that IPS is monophosphorylated at S524 and that the removal of this phosphate does not alter its enzymatic activity. These observations suggest a novel function for IPS in brain and other tissues. Future studies should resolve the functional role of phospho-IPS in brain inositol signaling.

Lakshmanan J.,Behavioral Science and Research Services | Lakshmanan J.,University of Louisville | Seelan R.S.,Behavioral Science and Research Services | Seelan R.S.,University of Louisville | And 8 more authors.
Journal of Proteomics and Bioinformatics | Year: 2012

Although lithium is widely used to treat Bipolar disorder (BD), its therapeutic role in BD is unclear. To gain insights into its mechanism of action we have used proteomic analysis to identify differentially expressed proteins in rat Prefrontal cortex (PFC), a region specifically affected in BD, after six weeks of lithium treatment. Proteins from control and lithium treated rat PFCs were separated by 2 Dimensional - Differential In-Gel Electrophoresis (2D-DIGE) and identified by mass spectrometry. Of the 2198 protein spots resolved, the abundance of 19 proteins was found to be significantly altered in the lithium treated group (with the levels of 5 proteins increasing and those of 14 decreasing). The levels of two protein spots exhibiting significant alteration after chronic lithium exposure were verified by Western blot analysis of rat PFC extracts. The 19 identified proteins represent novel targets for lithium action and participate in diverse functions that converge on a biological network that is specifically related to brain cell survival, prevention of neurodegeneration, and/or suppression of hyperactivity related signaling pathways. The identification of these targets should facilitate a better understanding of lithium's overall effect on mood control. © 2012 Lakshmanan J, et al.

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