Neurotransmitter ligands electrically excite neurons by activating ionotropic glutamate receptor (iGluR) ion channels. Knowledge of the iGluR amino acid residues that dominate ligand-induced activation would enable the prediction of function from sequence. We therefore explored the molecular determinants of activity in rat N-methyl-D-aspartate (NMDA)-type iGluRs (NMDA receptors), complex heteromeric iGluRs comprising two glycine-binding GluN1 and two glutamate-binding GluN2 subunits, using amino acid sequence analysis, mutagenesis, and electrophysiology. We find that a broadly conserved aspartate residue controls both ligand potency and channel activity, to the extent that certain substitutions at this position bypass the need for ligand binding in GluN1 subunits, generating NMDA receptors activated solely by glutamate. Furthermore, we identify a homomeric iGluR from the placozoan Trichoplax adhaerens that has utilized native mutations of this crucial residue to evolve into a leak channel that is inhibited by neurotransmitter binding, pointing to a dominant role of this residue throughout the iGluR superfamily.

神经递质配体通过激活离子型谷氨酸受体 (iGluR) 离子通道来电刺激神经元。了解主导配体诱导激活的 iGluR 氨基酸残基将能够根据序列预测功能。因此，我们利用氨基酸序列分析探索了大鼠 N-甲基-D-天冬氨酸 (NMDA) 型 iGluR（NMDA 受体）活性的分子决定因素，这是一种复杂的异聚 iGluR，包含两个甘氨酸结合 GluN1 和两个谷氨酸结合 GluN2 亚基。 、诱变和电生理学。我们发现广泛保守的天冬氨酸残基控制配体效力和通道活性，在某种程度上，该位置的某些取代绕过了配体在 GluN1 亚基中结合的需要，产生仅由谷氨酸激活的 NMDA 受体。此外，我们从长毛动物Trichoplax adhaerens中鉴定出同聚 iGluR ，它利用这一关键残基的天然突变演变成被神经递质结合抑制的泄漏通道，表明该残基在整个 iGluR 超家族中发挥主导作用。