Cheriyan John, Balsara Rashna D, Hansen Kasper B, Castellino Francis J
W. M. Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Department of Biomedical and Pharmaceutical Sciences, University of Montana, MT 59812, USA.
Neurosci Lett. 2016 Mar 23;617:240-6. doi: 10.1016/j.neulet.2016.02.032. Epub 2016 Feb 23.
The N-Methyl-D-Aspartate Receptors (NMDARs) are heteromeric cation channels involved in learning, memory, and synaptic plasticity, and their dysregulation leads to various neurodegenerative disorders. Recent evidence has shown that apart from the GluN1/GluN2A and GluN1/GluN2B diheteromeric ion channels, the NMDAR also exists as a GluN1/GluN2A/GluN2B triheteromeric channel that occupies the majority of the synaptic space. These GluN1/GluN2A/GluN2B triheteromers exhibit pharmacological and electrophysiological properties that are distinct from the GluN1/GluN2A and GluN1/GluN2B diheteromeric subtypes. However, these receptors have not been characterized with regards to their inhibition by conantokins, as well as their allosteric modulation by polyamines and extracellular protons. Here, we show that the GluN1/GluN2A/GluN2B triheteromeric channels showed less sensitivity to GluN2B-specific conantokin (con)-G and con-RlB, and subunit non-specific con-T, compared to the GluN2A-specific inhibitor TCN-201. Also, spermine modulation of GluN1/GluN2A/GluN2B triheteromers switched its nature from potentiation to inhibition in a pH dependent manner, and was 2.5-fold slower compared to the GluN1/GluN2B diheteromeric channels. Unraveling the distinctive functional attributes of the GluN1/GluN2A/GluN2B triheteromers is physiologically relevant since they form an integral part of the synapse, which will aid in understanding spermine/pH-dependent potentiation of these receptors in pathological settings.
N-甲基-D-天冬氨酸受体（NMDARs）是参与学习、记忆和突触可塑性的异聚阳离子通道，其功能失调会导致各种神经退行性疾病。最近的证据表明，除了GluN1/GluN2A和GluN1/GluN2B双异聚离子通道外，NMDAR还以GluN1/GluN2A/GluN2B三异聚通道的形式存在，该通道占据了大部分突触空间。这些GluN1/GluN2A/GluN2B三异聚体表现出与GluN1/GluN2A和GluN1/GluN2B双异聚亚型不同的药理学和电生理特性。然而，这些受体在被芋螺毒素抑制以及被多胺和细胞外质子变构调节方面尚未得到表征。在这里，我们表明，与GluN2A特异性抑制剂TCN-201相比，GluN1/GluN2A/GluN2B三异聚通道对GluN2B特异性芋螺毒素（con）-G和con-RlB以及亚基非特异性con-T的敏感性较低。此外，精胺对GluN1/GluN2A/GluN2B三异聚体的调节在pH依赖性方式下从增强转变为抑制，并且与GluN1/GluN2B双异聚通道相比慢2.5倍。阐明GluN1/GluN2A/GluN2B三异聚体独特的功能属性在生理上具有相关性，因为它们是突触的一个组成部分，这将有助于理解这些受体在病理环境中精胺/pH依赖性增强的机制。
