Homer is a postsynaptic scaffold protein, which has long and short isoforms. The long form of Homer consists of an N-terminal target-binding domain and a C-terminal multimerization domain, linking multiple proteins within a complex. The short form of Homer only has the N-terminal domain and likely acts as a dominant negative regulator. Homer2a, one of the long form isoforms of the Homer family, expresses with a transient peak in the early postnatal stage of mouse cerebellar granule cells (CGCs); however, the functions of Homer2a in CGCs are not fully understood yet. In this study, we investigated the physiological roles of Homer2a in CGCs using recombinant adenovirus vectors. Overexpression of the Homer2a N-terminal domain construct, which was made structurally reminiscent with Homer1a, altered NMDAR1 localization, decreased NMDA currents, and promoted the survival of CGCs. These results suggest that the Homer2a N-terminal domain acts as a dominant negative protein to attenuate NMDAR-mediated excitotoxicity. Moreover, we identified a novel short form N-terminal domain-containing Homer2, named Homer2e, which was induced by apoptotic stimulation such as ischemic brain injury. Our study suggests that the long and short forms of Homer2 are involved in apoptosis of CGCs.

中文翻译：

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Homer2a 及其新型短亚型 Homer2e 在 NMDA 受体介导的小脑颗粒细胞凋亡中的生理作用


Homer 是一种突触后支架蛋白，具有长亚型和短亚型。 Homer 的长形式由 N 端靶标结合结构域和 C 端多聚化结构域组成，连接复合物内的多个蛋白质。 Homer 的缩写形式仅具有 N 末端结构域，并且可能充当显性负调节因子。 Homer2a 是 Homer 家族的长亚型之一，在小鼠小脑颗粒细胞 (CGC) 的出生后早期出现瞬时峰值表达；然而，Homer2a 在 CGC 中的功能尚未完全了解。在本研究中，我们使用重组腺病毒载体研究了 Homer2a 在 CGC 中的生理作用。 Homer2a N 端结构域构建体的过度表达（其结构与 Homer1a 相似）改变了 NMDAR1 定位，降低了 NMDA 电流，并促进了 CGC 的存活。这些结果表明 Homer2a N 末端结构域作为显性负蛋白来减弱 NMDAR 介导的兴奋性毒性。此外，我们还发现了一种新的包含Homer2短型N端结构域的Homer2e，它是由缺血性脑损伤等细胞凋亡刺激诱导的。我们的研究表明 Homer2 的长形式和短形式参与 CGC 的凋亡。