Pregnanolone Sulfate Promotes Desensitization of Activated NMDA Receptors
Pregnanolone Sulfate Promotes Desensitization of Activated NMDA Receptors
复制标题
DOI：
10.1523/jneurosci.0281-09.2009
复制
发表时间：
2009-05-27
影响因子：
5.3
通讯作者：
Popescu, Gabriela K.
中科院分区：
文献类型：
--
作者：
Kussius, Cassandra L.;Kaur, Navjot;Popescu, Gabriela K.
神经类固醇是一种有效的神经调节剂，其作用部分是通过结合和改变神经递质门控通道的活性来实现的。孕酮硫酸酯(PAS)是一种内源性神经类固醇，可抑制NMDA受体，在体内具有神经保护作用。为了阐明孕烯醇酮硫酸盐抑制NMDA受体的机制，我们对单个GluN1/GluN2A受体记录的平衡单通道电流进行了动力学分析。结果表明，PAS(0.1 mM)仅通过将受体在闭合构象中花费的平均时间增加近5倍，就可以将单通道开放概率降低50%。根据这些数据，我们得出了一个动力学方案，总结了PAS对单通道动力学的影响，解释了PAS对宏观反应的影响，并导致我们提出PAS通过将活跃的受体转变为不敏感的构象来抑制NMDA受体的活性。这些发现强调了NMDA受体上的神经类固醇抑制部位是治疗兴奋性毒性病理包括急性和慢性神经变性的有价值的靶点。
Neurosteroids are potent neuromodulators which act in part by binding to and modifying the activity of neurotransmitter-gated channels. Pregnanolone sulfate (PAS) is an endogenous neurosteroid that inhibits NMDA receptors and is neuroprotective in vivo. To delineate the mechanism of NMDA receptor inhibition by pregnanolone sulfate we used kinetic analyses of equilibrium single-channel currents recorded from individual GluN1/GluN2A receptors. Results show that PAS (0.1 mM) reduces single-channel open probability by 50% solely by increasing similar to 5-fold the mean time spent by receptors in closed conformations. From these data we derive a kinetic scheme that summarizes the effects of PAS on single channel kinetics, accounts for the PAS effects on macroscopic responses and leads us to propose that PAS inhibits NMDA receptor activity by shifting active receptors into desensitized conformations. These findings highlight the neurosteroid inhibitory site on NMDA receptors as a valuable therapeutic target against excitotoxic pathologies including acute and chronic neurodegeneration.