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

精神分裂症是一种特发性疾病，可能是一种异质性疾病。 有证据表明，环状AMP第二信使的干扰 系统可能参与了精神分裂症的病理生理学过程。研究 使用死后脑组织显示cAMP生成增加 精神分裂症患者对NaF、GPP[NH]p和D_1受体激动剂的反应 患者与正常人的比较(Science 221：1304,1983)。类似的变化 已有报道在精神分裂症患者中评估环磷酸腺苷 在一个容易获取的组织来源中：血细胞。我们对该项目的兴趣 环状AMP第二信使系统涉及这样一个事实 中枢神经系统中的儿茶酚胺能神经元产生 主要通过激活第二信使系统发挥作用。这个 第二信使cAMP在细胞内受多巴胺(d1， D2)、去甲肾上腺素(β1、α2)和肾上腺素(β1、β2、α2)。 为了研究精神分裂症患者环磷酸腺苷的产生。 与对照组相比，我们启动了使用β淋巴细胞的研究， 已经被爱泼斯坦-巴尔病毒改变了。在我们组中，Dr。 库拉加将不和谐的双胞胎细胞转化为精神分裂症，并 来自无关的精神分裂症患者和正常人。我们觉得 这些电池的可用性为评估提供了理想的机会， 在受控环境下，第二信使系统的调节 精神分裂症患者。初步研究正在进行中，以评估 在这些转化的B中调节循环AMP积累的化合物 细胞。细胞在有或没有蛋白激酶C的情况下后退 激活剂，PMA，然后用Forsklin，霍乱毒素，PGE1， 异丙肾上腺素和多巴胺激动剂。作为响应的环状AMP的产生 用放射免疫法测定对这些药物的抑制作用。福斯科林、霍乱毒素、前列腺素E_1、 PMA、多巴胺和异丙肾上腺素增加这些细胞内cAMP的积聚 细胞。PMA对细胞的保护作用增强环磷酸腺苷 福斯可林、霍乱毒素、前列腺素E_1、异丙肾上腺素和 多巴胺。PMA的作用可被星状孢子素部分拮抗， 蛋白激酶C的抑制剂。这些初步结果表明 B细胞系是研究cAMP调控的有用模型 在人类细胞中。

Schizophrenia is an idiopathic and probably heterogenous disorder. Evidence suggest that disturbances in the cyclic AMP second messenger system may contribute to the pathophysiology of schizophrenia. Studies using postmortem brain tissue have shown enhanced cAMP production in response to NaF, Gpp[NH]p and a D1 receptor agonist in schizophrenic patients as compared to normals (Science 221:1304, 1983). Similar changes have been reported in schizophrenic patients when cyclic AMP is evaluated in a readily accessible source of tissue: blood cells. Our interest in the cyclic AMP second messenger system relates to the fact that catecholaminergic neurons in the central nervous system produce their effects predominantly through activation of second messenger systems. The second messenger, cyclic AMP, is regulated intracellularly by dopamine (D1, D2), norepinephrine (beta1, alpha2) and epinephrine (beta1, beta2, alpha2). In order to study cyclic AMP production in schizophrenic patients as compared to controls, we have initiated studies using beta-lymphocytes that have been transformed with the Epstein-Barr virus. In our group, Dr. Kulaga has transformed cells from twins discordant for schizophrenia, and from unrelated schizophrenic patients and normals. We feel that the availability of these cells offers an ideal opportunity for evaluating, under a controlled setting, the regulation of second messenger systems in schizophrenia patients. Initial studies are in process to evaluate compounds that regulate cyclic AMP accumulation in these transformed B cells. Cells were retreated with and without the protein kinase C activator, PMA, followed by treatment with forskolin, cholera toxin, PGE1, isoproterenol and dopamine agonists. The cyclic AMP production in response to these agents was measured using RIA. Forskolin, cholera toxin, PGE 1, PMA, dopamine and isoproterenol increased cyclic AMP accumulation in these cells. Pretreatment of the cells with PMA potentiated the cyclic AMP accumulation produced by forskolin, cholera toxin, pGE1, isoproterenol and dopamine. The effects of PMA were partially antagonized by staurosporin, an inhibitor of protein kinase C. These preliminary results indicate that the B cell lines are a useful model to study the regulation of cyclic AMP in human cells.