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.
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.
组胺增强天然和重组 N-甲基-D-天冬氨酸受体 (NMDAR) 的激活，但它在大脑中的作用机制和生理功能仍存在争议。使用四种不同的模型，我们进一步研究了组胺诱导的各种 NMDAR 介导的反应的增强作用。在单个培养的海马神经元中，组胺增强 NMDA 电流。它还增强了外源性 D-丝氨酸存在和饱和浓度时 NMDA 诱导的细胞内钙增加，表明其作用具有甘氨酸依赖性和甘氨酸非依赖性成分。在大鼠海马突触体中，组胺强烈增强 NMDA 诱导的[3H]去甲肾上腺素释放。该反应的特征包含在神经元或重组 NMDAR 中观察到的几种组胺介导的作用。它对微摩尔浓度的ifenprodil 敏感，具有 NR2B 选择性。它可以被脑中组胺的代谢产物 tele-methylhistamine 复制，并且可以被 histamine 在 NMDA 电流上的拮抗剂/inverse agonist impromidine 拮抗。到目前为止，组胺通常被认为与 NMDAR 的聚胺位点相互作用。然而， spermine 不会增强突触体中 NMDA 诱导的[3H]去甲肾上腺素释放，并且 tele-methylhistamine 对相同反应的增强作用不受聚胺拮抗剂 arcaine 的拮抗。在海马膜中，与 spermine 一样，tele-methylhistamine 增强[3H]dl-（E）-2-氨基-4-丙基-5-磷酸-3-戊烯酸（CGP39653）与谷氨酸位点的结合。相比之下，spermine 增加非平衡[3H]5H-二苯并[a，d]环庚烯-5,10-亚胺（dizocilpine 马来酸盐；MK-801）结合，并抑制[3H]ifenprodil 结合，而组胺和 tele-methylhistamine 没有影响。总之，在正常条件下，脑内组胺诱导的 NMDAR 增强作用发生。组胺不与聚胺位点结合，而是与所谓的 NMDAR 组胺结合位点结合。
