Identification of amino acid residues in GluR1 responsible for ligand binding and desensitization
Identification of amino acid residues in GluR1 responsible for ligand binding and desensitization
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DOI：
10.1523/jneurosci.21-09-03052.2001
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发表时间：
2001-05-01
影响因子：
5.3
通讯作者：
Pickering, DS
中科院分区：
文献类型：
--
作者：
Banke, TG;Greenwood, JR;Pickering, DS
虽然GluR 1（o）和GluR 3（o）在氨基酸水平上是同源的，但GluR 3（o）的脱敏速度比GluR 1（o）快约3倍。通过创建GluR 1（o）和GluR 3（o）的嵌合体并在其S2区进行点氨基酸交换，确定了两个残基对GluR 1（o）脱敏至关重要：Y 716和R/G RNA编辑位点R757。通过构建双点突变体（Y 716 F，R757 G）GluR 1（o），获得了GluR 1（o）与GluR 3（o）完全互换的脱敏率。此外，亚型选择性激动剂溴高鹅膏蕈氨酸的效力和亲和力都被Y 716 F突变所交换。提出了AMPA受体结合位点的一个模型，其中水分子的氢键矩阵在确定配体亲和力和受体脱敏特性中起着重要的作用。GluR 1中的残基Y 716和GluR 3中的残基F728与该基质差异性地相互作用以影响某些配体的结合亲和力，从而提供开发亚型选择性化合物的可能性。
Although GluR1(o) and GluR3(o) are homologous at the amino acid level, GluR3(o) desensitizes approximately threefold faster than GluR1(o). By creating chimeras of GluR1(o) and GluR3(o) and point amino acid exchanges in their S2 regions, two residues were identified to be critical for GluR1(o) desensitization: Y716 and the R/G RNA-edited site, R757. With creation of the double-point mutant (Y716F, R757G) GluR1(o), complete exchange of the desensitization rate of GluR1(o) to that of GluR3(o) was obtained. In addition, both the potency and affinity of the subtype-selective agonist bromohomoibotenic acid were exchanged by the Y716F mutation. A model is proposed of the AMPA receptor binding site whereby a hydrogen-bonding matrix of water molecules plays an important role in determining both ligand affinity and receptor desensitization properties. Residues Y716 in GluR1 and F728 in GluR3 differentially interact with this matrix to affect the binding affinity of some ligands, providing the possibility of developing subtype-selective compounds.