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 的长形式由一个 N 端靶结合域和一个 C 端多聚化域组成，连接复合物中的多个蛋白质。荷马的缩写形式只有 N 端结构域，可能充当主要的负调节剂。Homer2a 是 Homer 家族的长型亚型之一，在小鼠小脑颗粒细胞 (CGC) 的出生后早期以短暂的峰值表达；然而，尚未完全了解 Homer2a 在 CGC 中的功能。在这项研究中，我们使用重组腺病毒载体研究了 Homer2a 在 CGCs 中的生理作用。Homer2a N-末端结构域结构的过度表达，在结构上让人联想到 Homer1a，改变了 NMDAR1 定位，降低了 NMDA 电流，并促进 CGCs 的存活。这些结果表明，Homer2a N 末端结构域作为一种显性负蛋白来减弱 NMDAR 介导的兴奋性毒性。此外，我们发现了一种新的短形式的含有 N 端结构域的 Homer2，命名为 Homer2e，它是由缺血性脑损伤等凋亡刺激诱导的。我们的研究表明，Homer2 的长短形式与 CGC 的凋亡有关。