International Institute of Molecular and Cell Biology in Warsaw, 4 Ks. Trojdena Str., Warsaw 02-109, Poland.
International Institute of Molecular and Cell Biology in Warsaw, 4 Ks. Trojdena Str., Warsaw 02-109, Poland.
Biochim Biophys Acta Mol Cell Res. 2019 Jul;1866(7):1137-1150. doi: 10.1016/j.bbamcr.2019.01.007. Epub 2019 Jan 16.
Orai proteins form highly selective Ca release-activated channels (CRACs). They play a critical role in store-operated Ca entry (SOCE; i.e., the influx of external Ca that is induced by the depletion of endoplasmic reticulum Ca stores). Of the three Orai homologs that are present in mammals (Orai1-3), the physiological function of Orai1 is the best described. CRACs are formed by both homomeric assemblies and heteromultimers of Orais. Orai1 and Orai2 can form heteromeric channels that differ in conductivity during SOCE, depending on their Orai1-to-Orai2 ratio. The present study explored the potential consequences of ORAI1 overexpression in neurons where the dominant isoform is Orai2. We established the Tg(ORAI1)Ibd transgenic mouse line that overexpresses ORAI1 in brain neurons. We observed seizure-like symptoms in aged (≥15-month-old) female mice but not in males of the same age. The application of kainic acid and bicuculline to slices that were isolated from 8-month-old (±1 month) female Tg(ORAI1)Ibd mice revealed a significantly lower frequency of interictal bursts compared with samples that were isolated from wildtype mice. No differences were observed in male mice of a similar age. A battery of behavioral tests showed that context recognition decreased only in female transgenic mice. The phenotype that was observed in female mice suggests that ORAI1 overexpression may affect neuronal activity in a sex-dependent manner. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.
Orai 蛋白形成高度选择性的 Ca 释放激活通道 (CRACs)。它们在储存操作的 Ca 内流 (SOCE；即内质网 Ca 储存耗尽诱导的外部 Ca 流入) 中起着关键作用。在哺乳动物中存在的三种 Orai 同源物 (Orai1-3) 中，Orai1 的生理功能描述得最好。CRACs 是由同种 Orais 的同源二聚体和异源多聚体形成的。Orai1 和 Orai2 可以形成异源多聚体通道，在 SOCE 期间，根据它们的 Orai1 与 Orai2 的比值，通道的电导率不同。本研究探讨了在神经元中 ORAI1 过表达的潜在后果，其中优势同工型是 Orai2。我们建立了 Tg(ORAI1)Ibd 转基因小鼠系，该小鼠系在大脑神经元中过表达 ORAI1。我们观察到年龄较大（≥15 月龄）的雌性小鼠出现类似癫痫发作的症状，但年龄相同的雄性小鼠则没有。将 kainic 酸和 bicuculline 应用于从 8 月龄（±1 个月）的雌性 Tg(ORAI1)Ibd 小鼠分离的切片中，与从野生型小鼠分离的样本相比，发作间期爆发的频率明显降低。在年龄相似的雄性小鼠中则没有观察到差异。一系列行为测试表明，只有雌性转基因小鼠的情景识别能力下降。在雌性小鼠中观察到的表型表明，ORAI1 过表达可能以性别依赖的方式影响神经元活动。本文是由 Claus Heizmann、Joachim Krebs 和 Jacques Haiech 编辑的特刊“ECS Meeting”的一部分。
