Histamine potentiates N-methyl-D-aspartate receptors by interacting with an allosteric site distinct from the polyamine binding site

J Pharmacol Exp Ther. 2010 Mar;332(3):912-21. doi: 10.1124/jpet.109.158543. Epub 2009 Dec 15.


Histamine potentiates activation of native and recombinant N-methyl-d-aspartate receptors (NMDARs), but its mechanisms of action and physiological functions in the brain remain controversial. Using four different models, we have further investigated the histamine-induced potentiation of various NMDAR-mediated responses. In single cultured hippocampal neurons, histamine potentiated NMDA currents. It also potentiated the NMDA-induced increase in intracellular calcium in the absence, as well as with saturating concentrations, of exogenous d-serine, indicating both glycine-dependent and glycine-independent components of its effect. In rat hippocampal synaptosomes, histamine strongly potentiated NMDA-induced [(3)H]noradrenaline release. The profile of this response contained several signatures of the histamine-mediated effect at neuronal or recombinant NMDARs. It was NR2B-selective, being sensitive to micromolar concentrations of ifenprodil. It was reproduced by tele-methylhistamine, the metabolite of histamine in brain, and it was antagonized by impromidine, an antagonist/inverse agonist of histamine on NMDA currents. Up to now, histamine was generally considered to interact with the polyamine site of the NMDAR. However, spermine did not enhance NMDA-induced [(3)H]noradrenaline release from synaptosomes, and the potentiation of the same response by tele-methylhistamine was not antagonized by the polyamine antagonist arcaine. In hippocampal membranes, like spermine, tele-methylhistamine enhanced [(3)H]dl-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid (CGP39653) binding to the glutamate site. In contrast, spermine increased nonequilibrium [(3)H]5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate; MK-801) binding, and suppressed [(3)H]ifenprodil binding, whereas histamine and tele-methylhistamine had no effect. In conclusion, the histamine-induced potentiation of NMDARs occurs in the brain under normal conditions. Histamine does not bind to the polyamine site, but to a distinct entity, the so-called histamine site of the NMDAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / analogs & derivatives
  • 2-Amino-5-phosphonovalerate / pharmacology
  • Allosteric Site
  • Animals
  • Binding Sites
  • Calcium / metabolism
  • Dizocilpine Maleate / pharmacology
  • Drug Synergism
  • Hippocampus / metabolism
  • Histamine / pharmacology*
  • In Vitro Techniques
  • Intracellular Space / metabolism
  • Male
  • Methylhistamines / pharmacology
  • N-Methylaspartate / pharmacology
  • Neurons / metabolism
  • Norepinephrine / metabolism
  • Piperidines / pharmacology
  • Polyamines / metabolism*
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Spermine / pharmacology
  • Synaptosomes / metabolism


  • Methylhistamines
  • Piperidines
  • Polyamines
  • Receptors, N-Methyl-D-Aspartate
  • CGP 39653
  • Spermine
  • N-Methylaspartate
  • Dizocilpine Maleate
  • 2-Amino-5-phosphonovalerate
  • Histamine
  • tele-methylhistamine
  • ifenprodil
  • Calcium
  • Norepinephrine