Bongers Gerold, Sallmen Tina, Passani Maria Beatrice, Mariottini Chiara, Wendelin Dominique, Lozada Adrian, Marle André van, Navis Marjon, Blandina Patrizio, Bakker Remko A, Panula Pertti, Leurs Rob
Leiden/Amsterdam Center for Drug Research, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
J Neurochem. 2007 Oct;103(1):248-58. doi: 10.1111/j.1471-4159.2007.04752.x. Epub 2007 Jul 10.
Drugs targeting the histamine H(3) receptor (H(3)R) are suggested to be beneficial for the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. The H(3)R 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 H(3)R modulates the activity of the Akt/Glycogen synthase kinase 3beta (GSK-3beta) axis both in a constitutive and agonist-dependent fashion. H(3)R stimulation with the H(3)R 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 H(3)R-mediated activation of Akt can be inhibited by the H(3)R inverse agonist thioperamide, and by Wortmannin, LY294002 and PTX, suggesting the observed Akt activation occurs via a G(i/o)-mediated activation of phosphoinositide-3-kinase. H(3)R activation also results in the phosphorylation of Ser9 on GSK-3beta, which acts downstream of Akt and has a prominent role in brain function. In addition, we show the H(3)R-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 H(3)R adds new understanding to the roles of histamine and the H(3)R in brain function and pathology.
靶向组胺H(3)受体（H(3)R）的药物被认为对治疗神经退行性疾病有益，如阿尔茨海默病和帕金森病。H(3)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)和丝裂原活化蛋白激酶活性。在此我们表明，在转染的SK-N-MC细胞中，H(3)R以组成型和激动剂依赖性方式调节Akt/糖原合酶激酶3β（GSK-3β）轴的活性。用H(3)R激动剂依美哌啶刺激H(3)R可诱导Akt上Ser473和Thr308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。H(3)R介导的Akt激活可被H(3)R反向激动剂硫代哌啶以及渥曼青霉素、LY294002和百日咳毒素抑制，这表明观察到的Akt激活是通过G(i/o)介导的磷脂酰肌醇-3-激酶激活发生的。H(3)R激活还导致GSK-3β上Ser9的磷酸化，GSK-3β在Akt下游起作用，在脑功能中起重要作用。此外，我们表明H(3)R介导的Akt在Ser473处的磷酸化发生在原代大鼠皮层神经元和大鼠脑切片中。H(3)R这一信号特性的发现为组胺和H(3)R在脑功能和病理中的作用增添了新的认识。
