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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Corpus Striatum / metabolism
  • ErbB Receptors / metabolism
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • MAP Kinase Signaling System / physiology
  • Male
  • Neuroblastoma
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Histamine H3 / genetics
  • Receptors, Histamine H3 / metabolism*
  • Signal Transduction / physiology*
  • src-Family Kinases / metabolism


  • Receptors, Histamine H3
  • ErbB Receptors
  • src-Family Kinases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • GTP-Binding Protein alpha Subunits, Gi-Go