Phospholipase C, Ca2+, and calmodulin signaling are required for 5-HT2A receptor-mediated transamidation of Rac1 by transglutaminase.
Phospholipase C, Ca2+, and calmodulin signaling are required for 5-HT2A receptor-mediated transamidation of Rac1 by transglutaminase.
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磷脂酶C，Ca2+和钙调蛋白信号是通过转谷氨酰胺酶对RAC1进行的5-HT2A受体介导的转化。
DOI：
10.1007/s00213-010-1984-7
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发表时间：
2011-02
影响因子：
3.4
通讯作者：
Muma, Nancy A.
中科院分区：
文献类型：
--
作者：
Dai, Ying;Dudek, Nichole L.;Li, Qian;Muma, Nancy A.
关键词：
5-羟色胺，特别是5-羟色胺2A（5-HT 2A）受体信号传导在精神分裂症和情感障碍的病因学和治疗中是重要的。我们以前报道了一种新的5-HT 2A受体效应，增加转氨酶（TGase）催化的转酰胺，并激活小G蛋白Rac 1在A1 A1 v细胞，大鼠胚胎皮质细胞系。在这项研究中，我们探讨了5-HT 2A受体介导的Rac 1转酰胺的信号通路。用磷脂酶C（PLC）或钙调蛋白（CaM）的药理学抑制剂预处理A1 A1 v细胞，然后用5-HT 2A受体激动剂2，5-二甲氧基-4-碘苯丙胺（DOI）刺激。监测细胞内Ca 2+浓度和TGase修饰的Rac 1转酰胺作用。还评价了通过Ca 2+离子载体或螯合剂对Rac 1转酰胺基作用的细胞内Ca 2+操纵的效果。在与PLC抑制剂U 73122预处理的细胞中，DOI刺激的细胞内Ca 2+浓度的增加和TGase修饰的Rac 1显着衰减相比，与U 73343，一种无活性的类似物预处理。膜渗透性的Ca 2+螯合剂，BAPTA-AM强烈减少TGase催化的Rac 1转酰胺DOI刺激后。相反，Ca 2+离子载体离子霉素，在诱导细胞溶质Ca 2+升高到与DOI处理的细胞相当的水平的浓度下，产生TGase修饰的Rac 1的增加而没有5-HT 2A受体活化。此外，钙调素抑制剂W-7，显着降低Rac 1转酰胺在DOI处理的细胞中以剂量依赖性的方式。这些结果表明，5-HT 2A受体偶联PLC激活和随后的Ca 2+和CaM信号是必需的TGase催化的Rac 1转酰胺，和细胞内Ca 2+的增加是足以诱导Rac 1转酰胺。
Serotonin and especially serotonin 2A (5-HT2A) receptor signaling are important in the etiology and treatment of schizophrenia and affective disorders. We previously reported a novel 5-HT2A receptor effector, increased transglutaminase (TGase)-catalyzed transamidation, and activation of the small G protein Rac1 in A1A1v cells, a rat embryonic cortical cell line. In this study, we explore the signaling pathway involved in 5-HT2A receptor-mediated Rac1 transamidation. A1A1v cells were pretreated with pharmacological inhibitors of phospholipase C (PLC) or calmodulin (CaM), and then stimulated by the 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI). Intracellular Ca2+ concentration and TGase-modified Rac1 transamidation were monitored. The effect of manipulation of intracellular Ca2+ by a Ca2+ ionophore or a chelating agent on Rac1 transamidation was also evaluated. In cells pretreated with a PLC inhibitor U73122, DOI-stimulated increases in the intracellular Ca2+ concentration and TGase-modified Rac1 were significantly attenuated as compared to those pretreated with U73343, an inactive analog. The membrane-permeant Ca2+ chelator, BAPTA-AM strongly reduced TGase-catalyzed Rac1 transamidation upon DOI stimulation. Conversely, the Ca2+ ionophore ionomycin, at a concentration that induced an elevation of cytosolic Ca2+ to a level comparable to cells treated with DOI, produced an increase in TGase-modified Rac1 without 5-HT2A receptor activation. Moreover, the CaM inhibitor W-7, significantly decreased Rac1 transamidation in a dose-dependent manner in DOI-treated cells. These results indicate that 5-HT2A receptorcoupled PLC activation and subsequent Ca2+ and CaM signaling are necessary for TGase-catalyzed Rac1 transamidation, and an increase in intracellular Ca2+ is sufficient to induce Rac1 transamidation.
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影响因子：
9.8
作者：
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Walther DJ
影响因子：
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影响因子：
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作者：
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DOI：
10.1124/jpet.107.135046
发表时间：
2008-07-01
影响因子：
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作者：
Dai, Y.;Dudek, N. L.;Muma, N. A.
通讯作者：
Muma, N. A.
影响因子：
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作者：
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通讯作者：
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