GluN1 splice variant control of GluN1/GluN2D NMDA receptors
GluN1 splice variant control of GluN1/GluN2D NMDA receptors
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DOI：
10.1113/jphysiol.2012.234062
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发表时间：
2012-08-01
影响因子：
5.5
通讯作者：
Traynelis, Stephen F.
中科院分区：
文献类型：
--
作者：
Vance, Katie M.;Hansen, Kasper B.;Traynelis, Stephen F.
NMDA受体是离子型谷氨酸受体，其介导中枢神经系统中兴奋性突触传递的缓慢的、Ca 2+可渗透的组分。重组GluN 1 -1a/GluN 2D受体的特征在于低通道开放概率和去除激动剂后的失活时间过程延长。在这里，我们表明，失活的时间过程中，激动剂的效力，和单通道特性的GluN 2D-含有NMDA受体的GluN 1的可变RNA剪接调制。我们的研究结果表明，GluN 1外显子5，它编码的21个氨基酸的插入氨基末端结构域，是一个关键的决定因素，GluN 1/GluN 2D受体功能。GluN 1 -1b/GluN 2D受体含有外显子5编码的残基，以双指数时间过程失活，tau（FAST）为410 ms，tau（SLOW）为1100 ms。该时间过程比外显子5缺失的GluN 1 -1a/GluN 2D快3倍，其以1100 ms的tau（FAST）和3400 ms的tSLOW失活。含有外显子5的NMDA受体也具有比缺少外显子5的受体（0.017）高两倍的开放概率（0.037）。此外，GluN 1 -1b亚基内包含外显子5编码的残基会降低内源性激动剂L-谷氨酸的效力。含有突变型GluN 1 -1b亚基和野生型GluN 2D的NMDA受体的受体动力学评价确定GluN 1 -1b中的残基Lys 211是失活时间过程和谷氨酸效力的外显子5控制的关键决定因素。GluN 1/GluN 2D门控的动力学模型的评价表明，由外显子5编码的残基影响几个限速步骤。这些数据表明，GluN 1亚基是含GluN 2D的NMDA受体的动力学和药理学特性的关键决定因素。
NMDA receptors are ionotropic glutamate receptors that mediate a slow, Ca2+-permeable component of excitatory synaptic transmission in the central nervous system. Recombinant GluN1-1a/GluN2D receptors are characterized by low channel open probability and prolonged deactivation time course following the removal of agonist. Here, we show that the deactivation time course, agonist potency, and single channel properties of GluN2D-containing NMDA receptors are modulated by alternative RNA splicing of GluN1. Our results demonstrate that GluN1 exon 5, which encodes a 21-amino-acid insert in the amino-terminal domain, is a key determinant of GluN1/GluN2D receptor function. GluN1-1b/GluN2D receptors, which contain the residues encoded by exon 5, deactivate with a dual exponential time course described by a tau(FAST) of 410 ms and a tau(SLOW) of 1100 ms. This time course is 3-fold more rapid than that for exon 5-lacking GluN1-1a/GluN2D, which deactivates with a tau(FAST) of 1100 ms and a tSLOW of 3400 ms. Exon 5-containing NMDA receptors also have a two-fold higher open probability (0.037) than exon 5-lacking receptors (0.017). Furthermore, inclusion of exon 5-encoded residues within the GluN1-1b subunit decreases the potency for the endogenous agonist L-glutamate. Evaluation of receptor kinetics for NMDA receptors containing mutated GluN1-1b subunits and wild-type GluN2D identified residue Lys211 in GluN1-1b as a key determinant of exon 5 control of the deactivation time course and glutamate potency. Evaluation of a kinetic model of GluN1/GluN2D gating suggests that residues encoded by exon 5 influence several rate-limiting steps. These data demonstrate that the GluN1 subunit is a key determinant of the kinetic and pharmacological properties of GluN2D-containing NMDA receptors.