Histamine potentiates N-methyl-D-aspartate receptors by interacting with an allosteric site distinct from the polyamine binding site.
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.
Burban
A
A
Laboratoire de Neurobiologie et Pharmacologie Moléculaire, Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale, 2 ter rue d'Alésia, 75014 Paris, France.
Faucard
R
R
Armand
V
V
Bayard
C
C
Vorobjev
V
V
Arrang
J-M
JM
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000495:Allosteric Site; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004357:Drug Synergism; D006624:Hippocampus / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology*; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013096:Spermine / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism
D008761:Methylhistamines; D010880:Piperidines; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; C069052:CGP 39653; D013096:Spermine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D006632:Histamine; C020404:tele-methylhistamine; C010739:ifenprodil; D002118:Calcium; D009638:Norepinephrine