Regulation of m1 muscarinic receptors and nNOS mRNA levels by autoantibodies from schizophrenic patients
Regulation of m1 muscarinic receptors and nNOS mRNA levels by autoantibodies from schizophrenic patients
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DOI：
10.1016/j.neuropharm.2005.09.013
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发表时间：
2006-03-01
影响因子：
4.7
通讯作者：
Sterin-Borda, L
中科院分区：
文献类型：
--
作者：
Ganzinelli, S;Borda, T;Sterin-Borda, L
本文证明，精神分裂症患者的循环抗体与大脑M、M-1乙酰胆碱受体(M-1 mAChRs)相互作用，可诱导大鼠额叶皮质m(1)mAChR-mRNA和神经元型一氧化氮合酶(NNOS)基因的表达。对自身抗体作用过程中涉及的不同信号通路进行了表征。正如先前报道的那样，精神分裂症患者的血清自身抗体与神经细胞表面发生反应，抑制特定的mAChR放射性配基与大鼠大脑额叶皮质膜的结合。此外，以M-1合成肽(氨基酸序列与人M-1mAChR完全相同)为包被抗原，通过酶联免疫吸附试验证实了其与人脑M-1mAChR的第二细胞外环的反应性。经M-1mAChR刺激后，精神分裂症患者体内相应亲和纯化的抗M-1肽(抗M-1肽)m、mAChR-mRNA和nNOS-mRNA水平显著升高，并与磷脂酰肌醇(IP)的积聚和NOS的激活显著相关(α=0.05)。所有这些作用都被哌仑西平减弱，并模仿真正的激动剂的作用。同时分析nNOS、磷脂酶C(PLC)和钙/钙调蛋白(CaM)抑制对m(1)mAChR-mRNA和nNOS-mRNA水平的影响，表明抗体上调mRNA水平受内源性一氧化氮(NO)信号系统的控制。根据我们的结果，精神分裂症自身抗体激活M-1mAChR似乎诱导了nNOS-mRNA的表达，反过来，NOS的激活上调了RUT mAChR基因的表达。这些结果支持在特定的慢性精神分裂症患者中参与自身免疫过程。(C)2005年由爱思唯尔有限公司出版。
In this paper we demonstrate that, circulating antibodies from schizophrenic patients interacting with cerebral M, muscarinic acetylcholine receptors (M-1 mAChRs), can act as an inducer of m(1) mAChR-mRNA, and neuronal nitric oxide synthase (nNOS) mRNA gene expression of rat frontal cortex. The different signaling pathways involved in the autoantibody's actions, Were characterized. As previously reported serum autoantibodies from schizophrenic patients reacted against neural cells surface inhibiting the binding of the specific mAChR radioligand to rat cerebral frontal cortex membrane. Moreover, by ELISA using M-1 synthetic peptide (with identical aminoacid sequence to human M-1 mAChR) as coating antigen we demonstrated the reactivity against the second extracellular loop of human cerebral M-1 mAChR. The corresponding affinity-purified anti M-1 peptide IgG (anti M-1 peptide IgG) from schizophrenic patients by stimulation of M-1 mAChR exerted an increase in m, mAChR-mRNA and nNOS-mRNA levels, that significantly con-elated with the accumulation of phosphoinositides (IPs) and activation of NOS (alpha = 0.05). All these effects were blunted by pirenzepine and mimicked the action of the authentic agonist. Concurrent analysis of the effects of nNOS, phospholipase C (PLC) and calcium/calmodulin (CaM) inhibition on both, m(1) mAChR-mRNA and nNOS-mRNA levels, showing that antibody up-regulation mRNA level is under the control of endogenous nitric oxide (NO) signaling system. On the basis of our results, the activation of M-1 mAChR by schizophrenic autoantibody appears to induce nNOS-mRNA expression and reciprocally, the activation of NOS upregulates rut mAChR gene expression. These results gave support to the participation of an autoimmune process in a particular group of chronic schizophrenic patients. (c) 2005 Published by Elsevier Ltd.