REGULATION OF SECOND MESSENGER SYSTEMS IN EBV-TRANSFORMED B-CELL LINES

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Schizophrenia is an idiopathic and likely heterogenous disorder. Evidence suggests that disturbances in the cyclic AMP second messenger system may contribute to the pathophysiology of schizophrenia (Science 221:1304, 1983). We have initiated cyclic AMP studies using B- lymphocytes that have been transformed with the Epstein-Barr virus from schizophrenics and normals. Cells were pretreated with and without the protein kinase C activator, PMA, followed by treatment with forskolin, cholera toxin, PGE1, isoproterenol and dopamine agonists. PMA elevated basal cyclic AMP levels and enhanced isoproterenol-, prostaglandin E-1- (PGE-1), forskolin- and cholera toxin-stimulated cyclic AMP accumulation in Epstein-Barr Virus (EBV)-transformed human B-lymphocytes. Staurosporine, a PKC inhibitor, significantly antagonized the increase in cyclic AMP accumulation produced by PMA, whereas the inactive phorbol ester, 4a-phorbol 12,13 didecanoate (4aPDD), had no effect. Basal levels of cyclic AMP and the accumulation of cyclic AMP produced by PMA, isoproterenol, PGE-1, cholera toxin and the combination of these compounds with PMA were not significantly different between the schizophrenics and controls. The cyclic AMP response to forskolin in the presence and absence of PMA was significantly greater in EBV-transformed human B-lymphocytes from schizophrenics as compared with controls. These results indicate that activation of adenylyl cyclase by forskolin is elevated in EBV-transformed B-lymphocytes derived from schizophrenics and that this elevation is further enhanced through a protein kinase C (PKC) dependent phosphorylation mechanism. A multiple regression analysis revealed that the cyclic AMP responsiveness of EBV-transformed human B- lymphocytes to forskolin is associated with a linear combination of cell surface markers expressed on these cells. These results indicate that B cell lines are a useful model for the comparison of second messenger systems between schizophrenics and normals.