The Akt/GSK-3β axis as a new signaling pathway of the histamine H3 receptor
The Akt/GSK-3β axis as a new signaling pathway of the histamine H3 receptor
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DOI：
10.1111/j.1471-4159.2007.04752.x
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发表时间：
2007-10-01
影响因子：
4.7
通讯作者：
Leurs, Rob
中科院分区：
文献类型：
--
作者：
Bongers, Gerold;Sallmenj, Tina;Leurs, Rob
针对组胺H-3受体（H3 R）的药物被认为有益于治疗神经退行性疾病，如阿尔茨海默病和帕金森病。H3 R激活G（i/o）-蛋白以抑制腺苷酸环化酶活性并调节磷脂酶A（2）和MAPK活性。在此，我们表明，在转染的SK-N-MC细胞，H3 R调节Akt/糖原合成酶激酶3 β（GSK-3 β）轴的活性在组成和激动剂依赖的方式。用H3 R激动剂immepip刺激H3 R可诱导Akt上Ser 473和Thr 308的磷酸化，Akt是一种对神经元发育和功能很重要的丝氨酸/苏氨酸激酶。H3 R-介导的Akt活化可被H3 R反向激动剂硫代哌丁胺、Wortmannin、LY 294002和PTX抑制，表明观察到的Akt活化通过G（i/o）-介导的磷酸肌醇-3-激酶活化发生。H3 R活化还导致GSK-3 β上Ser 9的磷酸化，其作用于Akt的下游并且在脑功能中具有突出作用。此外，我们显示H3 R介导的Akt在Ser 473磷酸化发生在原代大鼠皮层神经元和大鼠脑切片。H3 R这种信号传导特性的发现为组胺和H3 R在脑功能和病理学中的作用增加了新的理解。
Drugs targeting the histamine H-3 receptor (H3R) are suggested to be beneficial for the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. The H3R activates G(i/o)-proteins to inhibit adenylyl cyclase activity and modulates phospholipase A(2) and MAPK activity. Herein we show that, in transfected SK-N-MC cells, the H3R modulates the activity of the Akt/Glycogen synthase kinase 3 beta (GSK-3 beta) axis both in a constitutive and agonist-dependent fashion. H3R stimulation with the H3R agonist immepip induces the phosphorylation of both Ser473 and Thr308 on Akt, a serine/threonine kinase that is important for neuronal development and function. The H3R-mediated activation of Akt can be inhibited by the H3R inverse agonist thioperamide, and by Wortmannin, LY294002 and PTX, suggesting the observed Akt activation occurs via a G(i/o)-mediated activation of phosphoinositicle-3-kinase. H3R activation also results in the phosphorylation of Ser9 on GSK-3 beta, which acts downstream of Akt and has a prominent role in brain function. In addition, we show the H3R-mediated phosphorylation of Akt at Ser473 to occur in primary rat cortical neurons and in rat brain slices. The discovery of this signaling property of the H3R adds new understanding to the roles of histamine and the H3R in brain function and pathology.