The Lurcher Mutation Identifies δ2 as an AMPA/Kainate Receptor-Like Channel That Is Potentiated by Ca2+
The Lurcher Mutation Identifies δ2 as an AMPA/Kainate Receptor-Like Channel That Is Potentiated by Ca2+
复制标题
Lurcher 突变将 δ2 识别为由 Ca2+ 增强的 AMPA/红藻氨酸受体样通道
作者：
L. Wollmuth;T. Kuner;C. Jatzke;P. Seeburg;N. Heintz;J. Zuo
Lurcher（Lc）小鼠的神经变性是由δ2（离子型谷氨酸受体（GluR）的亚基，具有未知的天然配体和通道特性）的组成性激活引起的。在人胚肾293细胞中表达的具有Lurcher突变（GluR-δ2Lc）的GluR-δ2的同源寡聚体通道显示出双重整流电流-电压关系，这让人联想到AMPA/红藻氨酸通道中的细胞内多胺阻断。类似地，由Ca 2+携带的总电流的分数为102 - 3%，与在Ca 2+可渗透的AMPA/红藻氨酸盐通道中发现的相当。通过GluR-δ2Lc通道的电流也被细胞外Ca 2+以双相方式增强，最大增强发生在生理浓度的Ca 2+。我们通过用精氨酸取代谷氨酰胺来检测GluR-δ2Lc中Q/R位点的功能作用。类似于AMPA/红藻氨酸受体，GluR-δ2Lc（R）通道没有显示出细胞内多胺的电压依赖性阻断，并且名义上对Ca 2+是不可渗透的。然而，由Ca 2+的增强作用保持不变。因此，GluR-δ 2Lc通道在功能上类似于AMPA/红藻氨酸受体通道，这与通道内衬M2和M3区段内的这些亚基共享的高序列同一性一致。此外，增强由Ca 2+和Ca 2+的渗透性与AMPA/红藻氨酸盐受体提供了一个可能的原因，细胞死亡的Lurcher小鼠，并可能有助于小脑长期抑郁症的生理条件下。
Neurodegeneration in Lurcher (Lc) mice results from constitutive activation of δ2, a subunit of ionotropic glutamate receptors (GluRs) with unknown natural ligands and channel properties. Homo-oligomeric channels of GluR-δ2 with the Lurcher mutation (GluR-δ2Lc) expressed in human embryonic kidney 293 cells showed a doubly rectifying current–voltage relation reminiscent of the block by intracellular polyamines in AMPA/kainate channels. Similarly, the fraction of the total current carried by Ca2+ was ∼2–3%, comparable with that found in Ca2+-permeable AMPA/kainate channels. Currents through GluR-δ2Lc channels were also potentiated by extracellular Ca2+ in a biphasic manner, with maximal potentiation occurring at physiological concentrations of Ca2+. We examined the functional role of the Q/R site in GluR-δ2Lc by replacing glutamine with arginine. Analogous to AMPA/kainate receptors, GluR-δ2Lc(R) channels showed no voltage-dependent block by intracellular polyamines and were nominally impermeable to Ca2+. The potentiation by Ca2+, however, remained intact. Hence, GluR-δ2Lcchannels are functionally similar to the AMPA/kainate receptor channels, consistent with the high-sequence identity shared by these subunits within the channel-lining M2 and M3 segments. Furthermore, potentiation by Ca2+ and a permeability to Ca2+ comparable with that of AMPA/kainate receptors provide a possible cause for cell death in Lurcher mice and may contribute to cerebellar long-term depression under physiological conditions.
影响因子：
3.5
作者：
HO, SN;HUNT, HD;PEASE, LR
通讯作者：
PEASE, LR