NMDA 受体电压依赖性门控和缓慢 Mg2+ 解锁的机制和结构决定因素。,Journal of Neuroscience

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NMDA 受体电压依赖性门控和缓慢 Mg2+ 解锁的机制和结构决定因素。
Journal of Neuroscience ( IF 4.4 ) Pub Date : 2013-02-27 , DOI: 10.1523/jneurosci.3712-12.2013
Richard J Clarke ₁ , Nathan G Glasgow , Jon W Johnson

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NMDA 受体 (NMDAR) 介导的电流依赖于膜去极化以缓解外部镁 (Mg(o)(2+)) 的强大电压依赖性 NMDAR 通道阻滞。Mg(o)(2+) 与天然 NMDAR 的解除阻塞表现出与快速 Mg(o)(2+) 解结合动力学一致的快速成分，以及较慢的毫秒时间尺度成分（慢速 Mg(o)(2+) ) 解除封锁)。在重组 NMDAR 中，缓慢的 Mg(o)(2+) 解阻在 GluN1/2A（由 GluN1 和 GluN2A 亚基组成的 NMDAR 亚型）和 GluN1/2B 受体中很突出，对 GluN1/2B 受体观察到的动力学较慢，但在 GluN1/2B 受体中不存在GluN1/2C 和 GluN1/2D 受体。缓慢的 Mg(o)(2+) 从 GluN1/2B 受体解除阻塞是由固有的电压依赖性门控导致的，这会增加去极化通道的开放概率。在这里，我们检查负责慢 Mg(o)(2+) 解锁的 NMDAR 亚型依赖性的机制。我们证明缓慢的 Mg(o)(2+) 从 GluN1/2A 受体（如 GluN1/2B 受体）解除阻塞是由固有的电压依赖性门控导致的。令人惊讶的是，GluN1/2A 和 GluN1/2B 受体表现出相同的固有电压依赖性；较快的 Mg(o)(2+) 解除 GluN1/2A 受体的阻断可以通过门控动力学中与电压无关的差异来解释。为了调查 GluN1/2C 和 GluN1/2D 受体中慢速 Mg(o)(2+) 的缺失，我们检查了 GluN2 S/L 站点，该站点负责几个 NMDAR 依赖于亚型的通道属性。将 GluN2A 亚基的 GluN2 S/L 位点从丝氨酸（在 GluN2A 和 GluN2B 亚基中发现）突变为亮氨酸（在 GluN2C 和 GluN2D 中发现）大大减少了电压依赖性门控和缓慢的 Mg(o)(2+) 解锁。因此，GluN2 S/L 站点上的残留物控制着慢速 Mg(o)(2+) 疏通和固有电压依赖性的表达。

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Mechanistic and structural determinants of NMDA receptor voltage-dependent gating and slow Mg2+ unblock.

NMDA receptor (NMDAR)-mediated currents depend on membrane depolarization to relieve powerful voltage-dependent NMDAR channel block by external magnesium (Mg(o)(2+)). Mg(o)(2+) unblock from native NMDARs exhibits a fast component that is consistent with rapid Mg(o)(2+) -unbinding kinetics and also a slower, millisecond time scale component (slow Mg(o)(2+) unblock). In recombinant NMDARs, slow Mg(o)(2+) unblock is prominent in GluN1/2A (an NMDAR subtype composed of GluN1 and GluN2A subunits) and GluN1/2B receptors, with slower kinetics observed for GluN1/2B receptors, but absent from GluN1/2C and GluN1/2D receptors. Slow Mg(o)(2+) unblock from GluN1/2B receptors results from inherent voltage-dependent gating, which increases channel open probability with depolarization. Here we examine the mechanisms responsible for NMDAR subtype dependence of slow Mg(o)(2+) unblock. We demonstrate that slow Mg(o)(2+) unblock from GluN1/2A receptors, like GluN1/2B receptors, results from inherent voltage-dependent gating. Surprisingly, GluN1/2A and GluN1/2B receptors exhibited equal inherent voltage dependence; faster Mg(o)(2+) unblock from GluN1/2A receptors can be explained by voltage-independent differences in gating kinetics. To investigate the absence of slow Mg(o)(2+) unblock in GluN1/2C and GluN1/2D receptors, we examined the GluN2 S/L site, a site responsible for several NMDAR subtype-dependent channel properties. Mutating the GluN2 S/L site of GluN2A subunits from serine (found in GluN2A and GluN2B subunits) to leucine (found in GluN2C and GluN2D) greatly diminished both voltage-dependent gating and slow Mg(o)(2+) unblock. Therefore, the residue at the GluN2 S/L site governs the expression of both slow Mg(o)(2+) unblock and inherent voltage dependence.

更新日期：2019-11-01

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