SIPA1L1/SPAR1 Interacts with the Neurabin Family of Proteins and is Involved in GPCR Signaling
SIPA1L1/SPAR1 Interacts with the Neurabin Family of Proteins and is Involved in GPCR Signaling
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DOI：
10.1523/jneurosci.0569-21.2022
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发表时间：
2022-03-23
影响因子：
5.3
通讯作者：
Akiyama, Tetsu
中科院分区：
文献类型：
--
作者：
Matsuura, Ken;Kobayashi, Shizuka;Akiyama, Tetsu
信号诱导增殖相关 1 (SIPA1) 样 1 (SIPA1L1；也称为 SPAR1) 作为 PSD-95/NMDA-R 复合体的组成部分，被认为可以调节突触功能，这些功能对于维持正常神经元活动非常重要，例如调节脊柱生长和突触缩放。然而，其生理作用仍知之甚少。在这里，我们使用超分辨率显微镜 (SRM) 在小鼠大脑中进行表达分析，并证明 SIPA1L1 主要定位于神经元的一般膜下区域，但令人惊讶的是，并不定位于 PSD。我们对小鼠大脑中 SIPA1L1 生理相互作用因子的筛选确定了亲旋蛋白和 neurabin-1（G 蛋白偶联受体 (GPCR) 信号传导的调节因子），但拒绝了 PSD-95/NMDA-R 复合物成分。此外，Sipa1l1(-/-) 小鼠表现出正常的脊柱大小分布和 NMDA-R 依赖性突触可塑性。然而，Sipa1l1(-/-)小鼠对α(2)-肾上腺素受体（亲旋蛋白靶标）或腺苷A1受体（神经蛋白-1靶标）激动剂刺激表现出异常反应，并出现显着的行为异常，例如多动、焦虑加剧、学习障碍、社交互动缺陷和癫痫发作易感性增强。所有实验均使用雄性小鼠。我们的研究结果揭示了 SIPA1L1 的意外特性，表明 SIPA1L1 缺陷可能与 GPCR 信号失调相关的神经精神疾病有关，例如癫痫、注意力缺陷多动障碍 (ADHD)、自闭症或脆性 X 综合征 (FXS)。
Signal-induced proliferation-associated 1 (SIPA1)-like 1 (SIPA1L1; also known as SPAR1) has been proposed to regulate synaptic functions that are important in maintaining normal neuronal activities, such as regulating spine growth and synaptic scaling, as a component of the PSD-95/NMDA-R-complex. However, its physiological role remains poorly understood. Here, we performed expression analyses using super-resolution microscopy (SRM) in mouse brain and demonstrated that SIPA1L1 is mainly localized to general submembranous regions in neurons, but surprisingly, not to PSD. Our screening for physiological interactors of SIPA1L1 in mouse brain identified spinophilin and neurabin-1, regulators of G-protein-coupled receptor (GPCR) signaling, but rejected PSD-95/NMDA-R-complex components. Furthermore, Sipa1l1(-/-) mice showed normal spine size distribution and NMDA-R-dependent synaptic plasticity. Nevertheless, Sipa1l1(-/-) mice showed aberrant responses to alpha(2)-adrenergic receptor (a spinophilin target) or adenosine A1 receptor (a neurabin-1 target) agonist stimulation, and striking behavioral anomalies, such as hyperactivity, enhanced anxiety, learning impairments, social interaction deficits, and enhanced epileptic seizure susceptibility. Male mice were used for all experiments. Our findings revealed unexpected properties of SIPA1L1, suggesting a possible association of SIPA1L1 deficiency with neuropsychiatric disorders related to dysregulated GPCR signaling, such as epilepsy, attention deficit hyperactivity disorder (ADHD), autism, or fragile X syndrome (FXS).