AMPA receptor flip/flop mutants affecting deactivation, desensitization, and modulation by cyclothiazide, aniracetam, and thiocyanate
AMPA receptor flip/flop mutants affecting deactivation, desensitization, and modulation by cyclothiazide, aniracetam, and thiocyanate
复制标题
DOI：
10.1523/jneurosci.16-21-06634.1996
复制
发表时间：
1996-11-01
影响因子：
5.3
通讯作者：
Mayer, ML
中科院分区：
文献类型：
--
作者：
Partin, KM;Fleck, MW;Mayer, ML
在GluRA(FliP)中构建了从Ser点到Asn、Ala、Asp、Gly、Gin、Met、Cys、Thr、Leu、Val和Tyr的点突变。后4个突变体没有功能；S750D只有在环噻嗪存在时才有活性，其余的突变体对谷氨酸的控制反应表现出不同的失活和脱敏速率，并显示出环噻嗪和阿尼拉西坦的差异调制。动力学分析的结果与阿尼拉西坦和环噻嗪的作用机理不同是一致的。我们的实验首次证明了残基750在调节内在通道门控动力学中的功能重要性，并强调了M3-M4细胞外环中选择性剪接的生物学意义。
AMPA receptor GluRA subunits with mutations at position 750, a residue shown previously to control allosteric regulation by cyclothiazide, were analyzed for modulation of deactivation and desensitization by cyclothiazide, aniracetam, and thiocyanate, Point mutations from Ser to Asn, Ala, Asp, Gly, Gin, Met, Cys, Thr, Leu, Val, and Tyr were constructed in GluRA(flip). The last four of these mutants were not functional; S750D was active only in the presence of cyclothiazide, and the remaining mutants exhibited altered rates of deactivation and desensitization for control responses to glutamate, and showed differential modulation by cyclothiazide and aniracetam. Results from kinetic analysis are consistent with aniracetam and cyclothiazide acting via distinct mechanisms. Our experiments demonstrate for the first time the functional importance of residue 750 in regulating intrinsic channel-gating kinetics and emphasize the biological significance of alternative splicing in the M3-M4 extracellular loop.