Thio L L, Clifford D B, Zorumski C F
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110.
J Neurosci. 1991 Nov;11(11):3430-41. doi: 10.1523/JNEUROSCI.11-11-03430.1991.
The quisqualate class of glutamate receptors is thought to play an important role in excitatory synaptic transmission, synaptic plasticity, and neuronal death. Since desensitization is a prominent feature of the responses mediated by this class of receptors, we have characterized the rapidly desensitizing quisqualate response in cultured postnatal rat hippocampal neurons using the whole-cell patch-clamp technique. Quisqualate and its structural analogs elicit a peak current that rapidly decays to a steady-state level. In contrast, currents induced by kainate, NMDA, and their structural analogs exhibit either no decay or a much slower decay. The biophysical and pharmacological properties of the peak and steady-state quisqualate currents indicate that both are mediated by an ionotropic quisqualate receptor. Quisqualate currents desensitized monoexponentially by approximately 70% with a time constant near 80 msec. Both the rate and percentage of desensitization showed slight voltage dependence and were concentration dependent, reaching maximal values at saturation. Additionally, the overlap of the dose-response curves for activation of the steady-state current and desensitization of the peak current by a conditioning dose suggests that the two processes are related. Furthermore, desensitizing quisqualate currents were observed when Ca2+, Mg2+, Na+, K+, and Cl- were removed from the extracellular solution or their concentrations greatly reduced. These results suggest that the decline in the response is not caused by a simple open channel block mechanism. Despite the lack of desensitization by kainate, our observations are consistent with the hypothesis that quisqualate and kainate act at a single receptor-channel complex. Kainate and quisqualate appeared to interact competitively when applied simultaneously and noncompetitively when quisqualate was applied first. In addition, saturating doses of quisqualate and kainate gave steady-state currents of equal amplitude in neurons treated with the lectin WGA, an inhibitor of quisqualate receptor desensitization.
谷氨酸受体的quisqualate类被认为在兴奋性突触传递、突触可塑性和神经元死亡中起重要作用。由于脱敏是这类受体介导的反应的一个突出特征，我们使用全细胞膜片钳技术对培养的新生大鼠海马神经元中快速脱敏的quisqualate反应进行了表征。quisqualate及其结构类似物引发一个峰值电流，该电流迅速衰减至稳态水平。相比之下，由海人酸、N-甲基-D-天冬氨酸及其结构类似物诱导的电流要么没有衰减，要么衰减要慢得多。峰值和稳态quisqualate电流的生物物理和药理学特性表明，两者均由离子型quisqualate受体介导。quisqualate电流以单指数形式脱敏约70%，时间常数接近80毫秒。脱敏的速率和百分比均表现出轻微的电压依赖性且呈浓度依赖性，在饱和时达到最大值。此外，通过一个预处理剂量激活稳态电流和使峰值电流脱敏的剂量反应曲线的重叠表明这两个过程是相关的。此外，当从细胞外溶液中去除Ca2+、Mg2+、Na+、K+和Cl-或其浓度大幅降低时，观察到了脱敏的quisqualate电流。这些结果表明，反应的下降不是由简单的开放通道阻断机制引起的。尽管海人酸不会引起脱敏，但我们的观察结果与quisqualate和海人酸作用于单一受体-通道复合物的假设一致。当同时应用海人酸和quisqualate时，它们似乎具有竞争性相互作用，而当先应用quisqualate时则表现为非竞争性相互作用。此外，在用凝集素WGA（一种quisqualate受体脱敏抑制剂）处理的神经元中，饱和剂量的quisqualate和海人酸产生了幅度相等的稳态电流。
