Williams K, Zappia A M, Pritchett D B, Shen Y M, Molinoff P B
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084.
Mol Pharmacol. 1994 May;45(5):803-9.
The endogenous polyamine spermine has multiple effects on the N-methyl-D-aspartate (NMDA) receptor. These include an increase in the magnitude of NMDA-induced whole-cell currents that is seen in the presence of saturating concentrations of glycine ("glycine-independent" stimulation), an increase in the affinity of the receptor for glycine ("glycine-dependent" stimulation), and voltage-dependent inhibition. Although many of the properties of native NMDA receptors are seen with homomeric NR1 receptors expressed in Xenopus oocytes, we have found that the effects of spermine are differentially regulated by NR2 subunits in heteromeric NR1/NR2 receptors. Glycine-independent stimulation by spermine occurred at homomeric NR1A receptors, which lack the amino-terminal insert in NR1, and at heteromeric NR1A/NR2B receptors but not at heteromeric NR1A/NR2A or NR1A/NR2C receptors. Glycine-independent stimulation was not seen at homomeric NR1B receptors, which include the amino-terminal insert in NR1, or at heteromeric receptors containing NR1B. Thus, glycine-independent stimulation by polyamines requires the presence of an NR1 variant, such as NR1A, that lacks the amino-terminal insert, but the manifestation of the stimulatory effect is controlled by the type of NR2 subunit present in a heteromeric complex. Glycine-dependent stimulation was seen at NR1A/NR2A and NR1A/NR2B receptors and may therefore involve a second polyamine binding site distinct from that which produces glycine-independent stimulation. The voltage-dependent inhibitory effect of spermine, which is more pronounced at hyperpolarized membrane potentials, occurred with similar magnitudes at NR1A/NR2A and NR1A/NR2B receptors but was absent at NR1A/NR2C receptors. Thus, NR2 subunits control both the stimulatory and inhibitory effects of spermine at NMDA receptors. Stimulation but not inhibition by spermine was seen at NR1A/NR2B receptors in the presence of extracellular Mg2+. Stimulation, seen in the presence of physiological concentrations of Ca2+ and Mg2+, may be the predominant effect of polyamines at NMDA receptors in the intact nervous system.
内源性多胺精胺对N-甲基-D-天冬氨酸（NMDA）受体具有多种作用。这些作用包括在存在饱和浓度甘氨酸的情况下，NMDA诱导的全细胞电流幅度增加（“甘氨酸非依赖性”刺激）、受体对甘氨酸的亲和力增加（“甘氨酸依赖性”刺激）以及电压依赖性抑制。尽管在非洲爪蟾卵母细胞中表达的同聚体NR1受体表现出许多天然NMDA受体的特性，但我们发现精胺的作用在异聚体NR1/NR2受体中受NR2亚基的差异调节。精胺对甘氨酸的非依赖性刺激发生在缺乏NR1氨基末端插入片段的同聚体NR1A受体以及异聚体NR1A/NR2B受体中，而在异聚体NR1A/NR2A或NR1A/NR2C受体中未出现。在包含NR1氨基末端插入片段的同聚体NR1B受体或含有NR1B的异聚体受体中未观察到甘氨酸非依赖性刺激。因此，多胺对甘氨酸的非依赖性刺激需要存在如NR1A这样缺乏氨基末端插入片段的NR1变体，但刺激作用的表现由异聚体复合物中存在的NR2亚基类型控制。在NR1A/NR2A和NR1A/NR2B受体中观察到甘氨酸依赖性刺激，因此可能涉及一个不同于产生甘氨酸非依赖性刺激的多胺结合位点。精胺的电压依赖性抑制作用在超极化膜电位时更为明显，在NR1A/NR2A和NR1A/NR2B受体中以相似幅度出现，但在NR1A/NR2C受体中不存在。因此，NR2亚基控制精胺对NMDA受体的刺激和抑制作用。在细胞外Mg2+存在的情况下，在NR1A/NR2B受体中观察到精胺的刺激作用而非抑制作用。在生理浓度的Ca2+和Mg2+存在时观察到的刺激作用可能是完整神经系统中多胺对NMDA受体的主要作用。
