The auxiliary subunits Neto1 and Neto2 have distinct, subunit-dependent effects at recombinant GluK1- and GluK2-containing kainate receptors.
The auxiliary subunits Neto1 and Neto2 have distinct, subunit-dependent effects at recombinant GluK1- and GluK2-containing kainate receptors.
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DOI：
10.1016/j.neuropharm.2015.08.018
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发表时间：
2015-12
影响因子：
4.7
通讯作者：
Fisher JL
中科院分区：
文献类型：
--
作者：
Fisher JL
红藻氨酸盐型离子型谷氨酸受体由5种不同的成孔亚基（GluK 1 -5）组合而成，具有不同的功能和药理学特性。这些受体也通过与辅助亚基Neto 1和Neto 2的共组装来调节。为了确定亚基组成的变化对红藻氨酸受体和Neto亚基之间的功能相互作用的影响，将Neto亚基与HEK-293 T细胞中的GluK 1或GluK 2组合，并通过膜片钳记录检查对谷氨酸的反应。GluK 1与Neto 1或Neto 2的共表达引起谷氨酸敏感性的大幅增加，并在低激动剂浓度下减缓脱敏的发生。然而，在较高的谷氨酸浓度下，Neto 2的主要作用是减缓脱敏的发生，而Neto 1的主要作用是增加脱敏的恢复。与此相反，与GluK 2同源受体的Neto 2的共表达对谷氨酸敏感性只有适度的影响，但增加了从脱敏中恢复的速率，以及在所有激动剂浓度下减缓其发作。嵌合Neto 1/Neto 2亚基的性质表明，细胞外N-末端区域，包括两个CUB结构域是主要负责不同的调节作用的Neto 1和Neto 2的GluK 1同源受体的脱敏特性。这些结果进一步表明，Neto亚基的功能效应取决于辅助亚基和成孔亚基的亚基身份。
The kainate-type of ionotropic glutamate receptors are assembled from a combination of five different pore-forming subunits (GluK1-5), which confer distinct functional and pharmacological properties. These receptors are also modulated by co-assembly with the auxiliary subunits Neto1 and Neto2. To determine the impact of variation in subunit composition on the functional interaction between kainate receptors and Neto subunits, the Neto subunits were combined with either GluK1 or GluK2 in HEK-293T cells and responses to glutamate examined through patch-clamp recordings. Co-expression of GluK1 with either Neto1 or Neto2 caused a substantial increase in glutamate sensitivity and a slowing of the onset of desensitization at low agonist concentrations. However, at higher glutamate concentrations the primary effect of Neto2 was to slow the onset of desensitization, while that of Neto1 was to increase recovery from desensitization. In contrast, co-expression of Neto2 with GluK2 homomeric receptors had only modest effects on glutamate sensitivity, but increased the rate of recovery from desensitization as well as slowing its onset at all agonist concentrations. The properties of chimeric Neto1/Neto2 subunits suggested that the extracellular N-terminal region including the two CUB domains was largely responsible for the distinct regulatory effects of Neto1 and Neto2 on the desensitization properties of GluK1 homomeric receptors. These results further demonstrate that the functional effects of Neto subunits depend upon the subunit identity of both the auxiliary and the pore-forming subunits.