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

精神分裂症是一种特发性的、可能是异质性的疾病。 证据表明，环状AMP第二信使中的干扰 系统可能有助于精神分裂症的病理生理学(科学 221：1304,1983)。我们已经启动了使用B-的环状AMP研究 用EB病毒转化的淋巴细胞来自 精神分裂症患者和正常人。对细胞进行预处理和不加药 蛋白激酶C激活剂，PMA，然后用Forsklin治疗， 霍乱毒素、前列腺素E_1、异丙肾上腺素和多巴胺激动剂。PMA升高 基础cAMP水平与异丙肾上腺素、前列腺素E-1升高 前列腺素E-1、福司可林和霍乱毒素刺激的环磷酸腺苷蓄积 在EB病毒(EBV)转化的人B淋巴细胞中。 蛋白激酶C抑制剂星形孢子素显著拮抗这种增加 在PMA产生的循环AMP积累中，而不活跃的佛波醇 4a-佛波酯(4a-phorbol 12，13-didecanate，4aPDD)无作用。基本水平 环状AMP和PMA产生的环状AMP的积累， 异丙肾上腺素、前列腺素E-1、霍乱毒素及其组合 含有PMA的化合物在 精神分裂症患者和对照组。环磷腺苷酶对福司可林的反应 在EBV转化的患者中，PMA的存在和缺失显著更多 精神分裂症患者外周血中B淋巴细胞与正常对照的比较这些 结果表明，Forskolin对腺酰环化酶的激活作用是 精神分裂症患者EBV转化的B淋巴细胞升高 这种升高通过蛋白激酶C(PKC)进一步增强 依赖的磷酸化机制。多元回归分析 显示EBV转化人B-亚群的环腺苷酸反应性 淋巴细胞到Forsklin与细胞的线性组合有关 这些细胞上表达的表面标志物。这些结果表明， B细胞系是比较第二信使的有用模型 精神分裂症患者和正常人之间的系统。

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.