Partin K M, Bowie D, Mayer M L
Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4495, USA.
Neuron. 1995 Apr;14(4):833-43. doi: 10.1016/0896-6273(95)90227-9.
The flip and flop splice variants of AMPA receptors show strikingly different sensitivity to allosteric regulation by cyclothiazide; heteromers assembled from GluR-A and GluR-B also exhibit splice variant-dependent differences in efficacy for activation by glutamate and kainate. The sensitivity for attenuation of desensitization by cyclothiazide for homomeric GluR-A was solely dependent upon exchange of Ser-750 (flip) and Asn-750 (flop), and was unaffected by mutagenesis of other divergent residues. In contrast, substantial alteration of the relative efficacy of glutamate versus kainate required mutation of multiple residues in the flip/flop region. Modulation by cyclothiazide was abolished by mutation of Ser-750 to Gin, the residue found at the homologous site in kainate-preferring subunits, whereas introduction of Ser at this site in GluR6 imparted sensitivity to cyclothiazide.
AMPA受体的翻转和摆动剪接变体对环噻嗪的变构调节表现出显著不同的敏感性；由GluR-A和GluR-B组装而成的异聚体在对谷氨酸和海人酸激活的效力方面也表现出剪接变体依赖性差异。环噻嗪对同聚体GluR-A脱敏作用的减弱敏感性仅取决于Ser-750（翻转）和Asn-750（摆动）的交换，并且不受其他不同残基诱变的影响。相比之下，谷氨酸与海人酸相对效力的显著改变需要在翻转/摆动区域对多个残基进行诱变。将Ser-750突变为Gln（在偏好海人酸的亚基同源位点发现的残基）会消除环噻嗪的调节作用，而在GluR6的该位点引入Ser会赋予对环噻嗪的敏感性。
