Desensitization and binding properties determine distinct alpha1beta2gamma2 and alpha3beta2gamma2 GABA(A) receptor-channel kinetic behavior.
Desensitization and binding properties determine distinct alpha1beta2gamma2 and alpha3beta2gamma2 GABA(A) receptor-channel kinetic behavior.
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脱敏和结合特性决定了不同的alpha1beta2gamma2和alpha3beta2gamma2 Gaba（A）受体通道动力学行为。
DOI：
10.1111/j.1460-9568.2007.05530.x
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发表时间：
2007-05
期刊：
影响因子：
--
通讯作者：
Vicini S
中科院分区：
文献类型：
--
作者：
Barberis A;Mozrzymas JW;Ortinski PI;Vicini S
由α1和α3亚基组成的GABAA受体亚型随着发育而变化，在成人大脑中具有特定的解剖定位。这些受体亚型先前已被证明在失活动力学上有很大差异，但潜在的门控机制尚未完全阐明。因此，我们在人胚胎肾293细胞中表达了大鼠α1β2γ2和α3β2γ2受体，并在宏观和单通道水平上记录了对超快GABA应用的电流反应。我们发现α3β2γ2介导电流的缓慢失活与相对较小的表观脱敏率和程度有关。相比之下，α1β2γ2受体介导的反应失活更快，脱敏更强。α3β2γ2受体在配对脉冲激动剂作用下比α1β2γ2通道恢复更快。在较宽的GABA浓度范围内，α3β2γ2受体介导的电流启动比α1β2γ2慢。单通道分析未发现α1β2γ2和α3β2γ2通道的开启/关闭动力学差异，但α3β2γ2受体的爆发持续时间更长。利用先前报道的动力学模型进行模拟，探讨了各自速率常数的差异。与α1β2γ2受体相比，主要动力学差异的再现需要更小的脱敏率以及α3β2γ2的结合和解结合率。我们的工作描述了两种主要GABAA受体亚型之间动力学差异的机制，并提供了一个解释天然GABA受体数据的框架。
GABAA receptor subtypes comprising the α1 and α3 subunits change with development and have a specific anatomical localization in the adult brain. These receptor subtypes have been previously demonstrated to greatly differ in deactivation kinetics but the underlying gating mechanisms have not been fully elucidated. Therefore, we expressed rat α1β2γ2 and α3β2γ2 receptors in human embryonic kidney 293 cells and recorded current responses to ultrafast GABA applications at macroscopic and single-channel levels. We found that the slow deactivation of α3β2γ2-mediated currents is associated with a relatively small rate and extent of apparent desensitization. In contrast, responses mediated by α1β2γ2 receptors had faster deactivation and stronger desensitization. α3β2γ2 receptors had faster recovery in the paired-pulse agonist applications than α1β2γ2 channels. The onset of currents mediated by α3β2γ2 receptors was slower than that of α1β2γ2 for a wide range of GABA concentrations. Single-channel analysis did not reveal differences in the opening/closing kinetics of α1β2γ2 and α3β2γ2 channels but burst durations were longer in α3β2γ2 receptors. Simulation with a previously reported kinetic model was used to explore the differences in respective rate constants. Reproduction of major kinetic differences required a smaller desensitization rate as well as smaller binding and unbinding rates in α3β2γ2 compared with α1β2γ2 receptors. Our work describes the mechanisms underlying the kinetic differences between two major GABAA receptor subtypes and provides a framework to interpret data from native GABA receptors.
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影响因子：
2.5
作者：
Ortinski, PI;Lu, CY;Vicini, S
通讯作者：
Vicini, S
影响因子：
2.5
作者：
Mozrzymas, JW;Barberis, A;Zarnowska, ED
通讯作者：
Zarnowska, ED
影响因子：
5.5
作者：
Hutcheon, B;Morley, P;Poulter, MO
通讯作者：
Poulter, MO
影响因子：
3.6
作者：
Barberis, A;Lu, CY;Mozrzymas, JW
通讯作者：
Mozrzymas, JW
影响因子：
16.2
作者：
MACONOCHIE, DJ;ZEMPEL, JM;STEINBACH, JH
通讯作者：
STEINBACH, JH