Williams K
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084.
Mol Pharmacol. 1994 Sep;46(3):531-41.
Histamine has numerous functions in the brain and has recently been shown to modulate responses of N-methyl-D-aspartate (NMDA) receptors on hippocampal neurons by a mechanism that does not involve classical histamine receptors. In the present work, voltage-clamp recording was used to study the effects of histamine on recombinant NMDA receptors expressed in Xenopus oocytes, to determine whether histamine acts directly on NMDA receptors and to investigate the subunit specificity of the effects of histamine. Histamine potentiated responses to NMDA at heteromeric NR1/NR2 receptors containing splice variants of the NR1 subunit (NR1A or NR1E) that lack the amino-terminal insert, together with the NR2B subunit but not the NR2A or NR2C subunit. Stimulation by histamine (EC50 = 10 microM) had a novel profile, involving a rapid increase in the magnitude of NMDA-induced currents followed by slow (approximately 1-min) desensitization to a steady state level. Desensitization of the response to histamine was time dependent and could occur in the absence of receptor activation by NMDA. Stimulation by histamine was dependent on the concentration of agonist used to activate NR1A/NR2B receptors and was seen with high but not low concentrations of NMDA and glutamate. The effect of histamine was not blocked by classical histamine receptor antagonists but was mimicked by the histamine metabolite 1-methylhistamine. At a high concentration (1 microM) histamine produced a voltage-dependent inhibition of NMDA currents at NR1A/NR2B receptors and at receptors (NR1B/NR2B) that are not sensitive to stimulation by histamine. The results suggest that histamine acts directly at a novel recognition site on some subtypes of NMDA receptors to increase their activity.
组胺在大脑中具有多种功能，最近研究表明，它可通过一种不涉及经典组胺受体的机制调节海马神经元上N-甲基-D-天冬氨酸（NMDA）受体的反应。在本研究中，采用电压钳记录法研究组胺对非洲爪蟾卵母细胞中表达的重组NMDA受体的影响，以确定组胺是否直接作用于NMDA受体，并研究组胺作用的亚基特异性。组胺增强了对NMDA的反应，该反应发生在含有缺乏氨基末端插入片段的NR1亚基（NR1A或NR1E）剪接变体以及NR2B亚基的异聚体NR1/NR2受体上，而不是在NR2A或NR2C亚基上。组胺刺激（EC50 = 10 microM）具有一种新的特征，包括NMDA诱导电流幅度迅速增加，随后缓慢（约1分钟）脱敏至稳态水平。对组胺反应的脱敏具有时间依赖性，并且可在无NMDA受体激活的情况下发生。组胺刺激取决于用于激活NR1A/NR2B受体的激动剂浓度，在高浓度而非低浓度的NMDA和谷氨酸存在时可见。组胺的作用未被经典组胺受体拮抗剂阻断，但可被组胺代谢产物1-甲基组胺模拟。在高浓度（1 microM）时，组胺对NR1A/NR2B受体以及对组胺刺激不敏感的受体（NR1B/NR2B）产生电压依赖性的NMDA电流抑制。结果表明，组胺直接作用于某些亚型NMDA受体上的一个新识别位点以增加其活性。
