Altered serine/threonine kinase activity in schizophrenia.

Converging evidence implicates alterations in multiple signaling pathways in the etiology of schizophrenia. Previously, these studies were limited to the analysis of one or a few phosphoproteins at a time. Here, we use a novel kinase array platform to simultaneously investigate the convergence of multiple signaling cascades implicated in schizophrenia. This technology uses consensus peptide substrates to assess activity levels of a large number (>100) of serine/threonine protein kinases. 19 peptide substrates were differentially phosphorylated (>15% change) in the frontal cortex in schizophrenia. These peptide substrates were examined using Ingenuity Pathway Analysis to group them according to the functions and to identify processes most likely affected in schizophrenia. Pathway analysis placed 14 of the 19 peptides into cellular homeostatic pathways, 10 into pathways governing cytoskeletal organization, and 8 into pathways governing ion homeostasis. These data are the first to simultaneously investigate comprehensive changes in signaling cascades in a severe psychiatric disorder. The examination of kinase activity in signaling pathways may facilitate the identification of novel substrates for drug discovery and the development of safer and more effective pharmacological treatment for schizophrenia.