Mechanisms of Modal Activation of GluA3 Receptors
Mechanisms of Modal Activation of GluA3 Receptors
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DOI：
10.1124/mol.111.071688
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发表时间：
2011-07-01
影响因子：
3.6
通讯作者：
Oswald, Robert E.
中科院分区：
文献类型：
--
作者：
Poon, Kinning;Ahmed, Ahmed H.;Oswald, Robert E.
AMPA受体是中枢神经系统中主要的兴奋性神经递质受体，并且参与许多神经系统疾病。激动剂结合位点存在于形成功能通道的四个亚基中的每一个中。结合由三个步骤组成：激动剂与双叶配体结合结构域（LBD）对接，LBD闭合，以及通过叶间氢键增加闭合叶构象的稳定性。我们描述了GluA3单通道电流激活的硝基威拉德（NO2W）和chlorowillardiine（ClW）在环噻嗪的存在下，结合晶体结构的GluA2和GluA3 LBD绑定到fluorowillardiine（FW），ClW，NO2W。当与NO2W或ClW结合时，GluA3通道以相当的开放概率打开至三个电导水平，并显示出与用谷氨酸和FW作为激动剂获得的模式行为相似的模式行为（Poon et al.，2010年）。在较低的浓度下，ClW诱发了交替的动力学行为，包括在较低的电导状态下的高开放概率。与GluA3 LBD结合的ClW的结构表现出独特的部分开放的氢键结构，这可能与这些替代动力学有关。NO2W诱发的开放时间比其他激动剂在高和非常高的模式。与NO2W结合的GluA2 LBD的结构表现出完全封闭的叶，具有由硝基介导的额外叶间相互作用。除了完全激动剂和部分激动剂之间的功效差异之外，AMPA受体的单通道行为的复杂性也可能与改变各种闭合程度的稳定性的小的相互作用有关。
AMPA receptors are the major excitatory neurotransmitter receptors in the central nervous system and are involved in numerous neurological disorders. An agonist-binding site is present in each of four subunits that form a functional channel. Binding consists of three steps: docking of agonist to the bilobed ligand binding domain (LBD), closure of the LBD, and increased stability of the closed-lobe conformation through interlobe hydrogen bonding. We describe GluA3 single channel currents activated by nitrowillardiine (NO2W) and chlorowillardiine (ClW) in the presence of cyclothiazide, in conjunction with crystal structures of GluA2 and GluA3 LBDs bound to fluorowillardiine (FW), ClW, and NO2W. When bound to NO2W or ClW, the GluA3 channel opens to three conductance levels with comparable open probabilities and displays modal behavior similar to that obtained with glutamate and FW as agonists (Poon et al., 2010). At lower concentrations, ClW evoked an alternate kinetic behavior, consisting of high open probability in lower conductance states. The structure of ClW bound to GluA3 LBD exhibits a unique partially open hydrogen bonding structure that may be associated with these alternative kinetics. NO2W evoked longer open times than seen for other agonists in high and very high modes. The structure of GluA2 LBD bound to NO2W exhibits fully closed lobes with additional interlobe interactions mediated by the nitro group. Beyond differences in efficacy between full and partial agonists, the complexities of the single channel behavior of AMPA receptors may also be associated with small interactions that modify the stability of various degrees of closure.