The Akt-GSK-3 beta axis as a new signaling pathway of the histamine H sub(3) receptor

Drugs targeting the histamine H sub(3) receptor (H sub(3)R) are suggested to be beneficial for the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. The H sub(3)R activates G sub(i-o)-proteins to inhibit adenylyl cyclase activity and modulates phospholipase A sub(2) and MAPK activity. Herein we show that, in transfected SK-N-MC cells, the H sub(3)R modulates the activity of the Akt-Glycogen synthase kinase 3 beta (GSK-3 beta ) axis both in a constitutive and agonist-dependent fashion. H sub(3)R stimulation with the H sub(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 sub(3)R-mediated activation of Akt can be inhibited by the H sub(3)R inverse agonist thioperamide, and by Wortmannin, LY294002 and PTX, suggesting the observed Akt activation occurs via a G sub(i-o)-mediated activation of phosphoinositide-3-kinase. H sub(3)R 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 H sub(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 sub(3)R adds new understanding to the roles of histamine and the H sub(3)R in brain function and pathology.