Cyclothiazide differentially modulates desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor splice variants.
Cyclothiazide differentially modulates desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor splice variants.
复制标题
Cyclothiazide 差异调节 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体剪接变体的脱敏。
作者：
K. Partin;D. K. Patneau;M. Mayer
环噻嗪对α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体亚基GluR-A、-C和-D翻转剪接变体的激动剂反应比翻转形式的激动剂反应更强。环噻嗪对GluR-Aflop的增强作用显示出更大的功效和更高的表观亲和力。与翻转剪接变体的较高亲和力一致，GluR-Aflip从环噻嗪增强中的恢复比GluR-Aflop慢30倍。在300 μ M环噻嗪存在下，GluR-Aflip而不是GluR-Aflop的红藻氨酸剂量-反应曲线的6倍红移另外有助于这些剪接变体的增强差异。虽然对照组对谷氨酸的反应显示GluR-A的两种剪接变体的强烈脱敏，但在100 μ M环噻嗪存在下，GluR-Aflip的脱敏强烈减弱，而GluR-Aflop的脱敏仍然明显，但与对照组相比，发病率减慢了50倍。在由GluR-A和GluR-B形成的异聚AMPA受体中，翻转剪接变体对于控制从对红藻氨酸的响应的增强的恢复和对谷氨酸的响应的脱敏的阻断两者都是占优势的。我们的研究结果表明，触发器/触发器模块可以直接有助于环噻嗪的结合位点，提高了该位点位于细胞外受体结构域的可能性。
Agonist responses for flip splice variants of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR-A, -C, and -D are more strongly potentiated by cyclothiazide than are those for the flop forms. Cyclothiazide shows both greater efficacy and higher apparent affinity for potentiation of GluR-Aflip versus GluR-Aflop. Consistent with higher affinity for the flip splice variant, recovery from potentiation by cyclothiazide proceeds 30 times more slowly for GluR-Aflip than for GluR-Aflop. In the presence of 300 microM cyclothiazide a 6-fold leftward shift in the kainate dose-response curve for GluR-Aflip but not GluR-Aflop additionally contributes to a difference in potentiation for these splice variants. Although control responses to glutamate show strong desensitization for both splice variants of GluR-A, in the presence of 100 microM cyclothiazide desensitization is strongly attenuated for GluR-Aflip, whereas for GluR-Aflop desensitization remains pronounced but with a rate of onset slowed 50-fold, compared with control. In heteromeric AMPA receptors formed from GluR-A and GluR-B, the flip splice variants are dominant for controlling both recovery from potentiation of responses to kainate and block of desensitization of responses to glutamate. Our results suggest that the flip/flop module could directly contribute to the binding site for cyclothiazide, raising the possibility that this site is located in an extracellular receptor domain.