Neurosteroid binding to the amino terminal and glutamate binding domains of ionotropic glutamate receptors
Neurosteroid binding to the amino terminal and glutamate binding domains of ionotropic glutamate receptors
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DOI：
10.1016/j.steroids.2012.03.011
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发表时间：
2012-06-01
期刊：
影响因子：
2.7
通讯作者：
Gentile, Lisa
中科院分区：
文献类型：
--
作者：
Cameron, Krasnodara;Bartle, Emily;Gentile, Lisa
内源性内源性神经甾体，硫酸双烯醇酮（PS）和3 α-羟基-5 β-葡聚糖-20-酮硫酸盐（PREGAS），已被证明差异调节离子型谷氨酸受体（iGluR）家族的配体门控离子通道。在与这些受体结合后，PREGAS降低通过通道的电流。在与含有GluN 2C或GluN 2D亚基的非NMDA或NMDA受体结合后，PS也降低通过通道的电流，然而，在与含有GluN 2A或GluN 2B亚基的NMDA受体结合后，通过通道的电流增加。为了开始理解这种差异调节，我们克隆了NMDA GluN 2B和GluN 2D以及AMPA GluA 2亚基的5152和氨基末端结构域（ATD）。在这里，我们提出的结果表明，PS和PREGAS结合到不同的网站在ATD的GluA 2亚基，这与我们实验室以前的结果相结合时，现在确定两个结合域的每个神经类固醇。我们还表明，这两种神经甾体仅与GluN 2D亚基的AID结合，这表明这种结合与AMPA GluA 2亚基的结合不同，两者都导致iGluR抑制。最后，我们提供的证据表明，PS和PREGAS结合到NMDA GluN 2B亚基的S1 S2结构域。神经类固醇与负责增强iGluR的NMDA亚基的S1 S2结构域和负责抑制iGluR的NMDA亚基的ATD结合，为治疗设计提供了一个有趣的选择。(C)2012 Elsevier Inc. All rights reserved.
The endogenous endogenous neurosteroids, pregnenolone sulfate (PS) and 3 alpha-hydroxy-5 beta-pregnan-20-one sulfate (PREGAS), have been shown to differentially regulate the ionotropic glutamate receptor (iGluR) family of ligand-gated ion channels. Upon binding to these receptors, PREGAS decreases current flow through the channels. Upon binding to non-NMDA or NMDA receptors containing an GluN2C or GluN2D subunit, PS also decreases current flow through the channels, however, upon binding to NMDA receptors containing an GluN2A or GluN2B subunit, flow through the channels increases. To begin to understand this differential regulation, we have cloned the 5152 and amino terminal domains (ATD) of the NMDA GluN2B and GluN2D and AMPA GluA2 subunits. Here we present results that show that PS and PREGAS bind to different sites in the ATD of the GluA2 subunit, which when combined with previous results from our lab, now identifies two binding domains for each neurosteroid. We also show both neurosteroids bind only to the AID of the GluN2D subunit, suggesting that this binding is distinct from that of the AMPA GluA2 subunit, with both leading to iGluR inhibition. Finally, we provide evidence that both PS and PREGAS bind to the S1S2 domain of the NMDA GluN2B subunit. Neurosteroid binding to the S1S2 domain of NMDA subunits responsible for potentiation of iGluRs and to the ATD of NMDA subunits responsible for inhibition of iGluRs, provides an interesting option for therapeutic design. (C) 2012 Elsevier Inc. All rights reserved.