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首页> 外文期刊>Molecular pharmacology. >A regulatory domain (R1-R2) in the amino terminus of the N-methyl-D-aspartate receptor: effects of spermine, protons, and ifenprodil, and structural similarity to bacterial leucine/isoleucine/valine binding protein.
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A regulatory domain (R1-R2) in the amino terminus of the N-methyl-D-aspartate receptor: effects of spermine, protons, and ifenprodil, and structural similarity to bacterial leucine/isoleucine/valine binding protein.

机译：N-甲基-D-天冬氨酸受体的氨基末端的调节域（R1-R2）：精胺，质子和艾芬地尔的作用以及与细菌亮氨酸/异亮氨酸/缬氨酸结合蛋白的结构相似性。

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摘要

There are complex interactions between spermine, protons, and ifenprodil at N-methyl-D-aspartate receptors. Spermine stimulation may involve relief of proton inhibition, whereas ifenprodil inhibition may involve an increase in proton inhibition. We studied mutations at acidic residues in the NR1 subunit using voltage-clamp recording of NR1/NR2B receptors expressed in Xenopus oocytes. Mutations at residues near the site of the exon-5 insert, including E181 and E185, reduced spermine stimulation and proton inhibition. Mutation NR1(D130N) reduced sensitivity to ifenprodil by more than 500-fold, but had little effect on sensitivity to spermine and pH. Mutations at six other residues in this region of the NR1 subunit reduced the potency and, in some cases, the maximum effect of ifenprodil. These mutants did not affect sensitivity to pH, glutamate, glycine, or other hallmark properties of N-methyl-D-aspartate channels such as Mg2+ block and Ba2+ permeability. Residues in this region presumably form part of the ifenprodil-binding site. To model this region of NR1 we compared the predicted secondary structure of NR1 (residues 19-400) with the known structures of 1,400 proteins. This region of NR1 is most similar to bacterial leucine/isoleucine/valine binding protein, a globular amino acid binding protein containing two lobes, similar to the downstream S1-S2 region of glutamate receptors. We propose that the tertiary structure of NR1(22-375) is similar to leucine/isoleucine/valine binding protein, containing two "regulatory" domains, which we term R1 and R2. This region, which contains the binding sites for spermine and ifenprodil, may influence the downstream S1 and S2 domains that constitute the glycine binding pocket.
机译：在N-甲基-D-天冬氨酸受体上，精胺，质子和艾芬地尔之间存在复杂的相互作用。精胺刺激可能涉及质子抑制的减轻，而艾芬地尔抑制可能涉及质子抑制的增加。我们使用爪蟾卵母细胞中表达的NR1 / NR2B受体的电压钳记录研究了NR1亚基中酸性残基的突变。在外显子5插入位点附近的残基处的突变，包括E181和E185，减少了精胺刺激和质子抑制。突变NR1（D130N）对艾芬地尔的敏感性降低了500倍以上，但对精胺和pH的敏感性影响很小。 NR1亚基这一区域其他六个残基的突变降低了效力，在某些情况下降低了艾芬地尔的最大作用。这些突变体不影响对pH，谷氨酸，甘氨酸或N-甲基-D-天冬氨酸通道的其他标志性特性（如Mg2 +阻滞和Ba2 +渗透性）的敏感性。该区域中的残基大概形成了艾芬地尔结合位点的一部分。为了模拟NR1的这一区域，我们将NR1的预测二级结构（残基19-400）与已知的1,400种蛋白质结构进行了比较。 NR1的这一区域与细菌亮氨酸/异亮氨酸/缬氨酸结合蛋白最相似，后者是一种含有两个叶的球状氨基酸结合蛋白，与谷氨酸受体的下游S1-S2区相似。我们提出，NR1（22-375）的三级结构类似于亮氨酸/异亮氨酸/缬氨酸结合蛋白，其中包含两个“调节”结构域，我们将其称为R1和R2。包含精胺和艾芬地尔的结合位点的该区域可能影响构成甘氨酸结合口袋的下游S1和S2结构域。

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