Protons Potentiate GluN1/GluN3A Currents by Attenuating Their Desensitisation.
Protons Potentiate GluN1/GluN3A Currents by Attenuating Their Desensitisation.
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DOI：
10.1038/srep23344
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发表时间：
2016-03-22
影响因子：
4.6
通讯作者：
Popescu GK
中科院分区：
文献类型：
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作者：
Cummings KA;Popescu GK
n -甲基- d -天冬氨酸（NMDA）受体是由两个GluN1和两个GluN2或/和GluN3亚基组成的谷氨酸和甘氨酸门控通道。GluN3A的表达受发育调控，这种正常表达模式的改变发生在几种脑部疾病中，通过未知的机制改变突触的成熟和功能。在NMDA受体家族中，GluN1/GluN3受体产生甘氨酸门控的深度脱敏电流，对谷氨酸和NMDA不敏感；这些电流的特征仍然很差，它们的细胞功能也是未知的。在这里，我们发现细胞外酸化强烈增强了重组GluN1/GluN3A受体的甘氨酸门控电流，在生理pH范围内的影响是一半最大的。这主要是由于较慢的电流脱敏和脱敏后较快的电流恢复，并且是由面对配体结合域异二聚体界面的残基介导的。与观察到的脱敏动力学变化一致，酸性转移增加了GluN1/GluN3A平衡电流，并以甘氨酸浓度依赖的方式使膜去极化。这些结果揭示了GluN1/GluN3A受体的新的调节机制，进一步将其与典型的谷氨酸能GluN1/GluN2受体区分开来，并为天然制剂中GluN1/GluN3A电流的检测、鉴定和进一步研究提供了新的有效的药理学工具。
N-methyl-D-aspartate (NMDA) receptors are glutamate- and glycine-gated channels composed of two GluN1 and two GluN2 or/and GluN3 subunits. GluN3A expression is developmentally regulated, and changes in this normal pattern of expression, which occur in several brain disorders, alter synaptic maturation and function by unknown mechanisms. Uniquely within the NMDA receptor family, GluN1/GluN3 receptors produce glycine-gated deeply desensitising currents that are insensitive to glutamate and NMDA; these currents remain poorly characterised and their cellular functions are unknown. Here, we show that extracellular acidification strongly potentiated glycine-gated currents from recombinant GluN1/GluN3A receptors, with half-maximal effect in the physiologic pH range. This was largely due to slower current desensitisation and faster current recovery from desensitisation, and was mediated by residues facing the heterodimer interface of the ligand-binding domain. Consistent with the observed changes in desensitisation kinetics, acidic shifts increased the GluN1/GluN3A equilibrium current and depolarized the membrane in a glycine concentration-dependent manner. These results reveal novel modulatory mechanisms for GluN1/GluN3A receptors that further differentiate them from the canonical glutamatergic GluN1/GluN2 receptors and provide a new and potent pharmacologic tool to assist the detection, identification, and the further study of GluN1/GluN3A currents in native preparations.