GPR3 expression in retinal ganglion cells contributes to neuron survival and accelerates axonal regeneration after optic nerve crush in mice
GPR3 expression in retinal ganglion cells contributes to neuron survival and accelerates axonal regeneration after optic nerve crush in mice
复制标题
DOI：
10.1016/j.nbd.2022.105811
复制
发表时间：
2022-07
影响因子：
6.1
通讯作者：
Shun Masuda;Shigeru Tanaka;Hiroko Shiraki;Y. Sotomaru;Kana Harada;I. Hide;Y. Kiuchi;N. Sakai
中科院分区：
文献类型：
--
作者：
Shun Masuda;Shigeru Tanaka;Hiroko Shiraki;Y. Sotomaru;Kana Harada;I. Hide;Y. Kiuchi;N. Sakai
青光眼是一种视神经病变，是目前最常见的导致不可逆失明的疾病之一。在视网膜神经节神经元丧失之前发生的轴突变性被认为参与青光眼的发病机制。G蛋白偶联受体3（GPR3）属于A类视紫红质型GPCR家族，在多种神经元中高度表达。GPR3在其无配体的情况下组成性激活Gαs蛋白的能力方面是独特的，这提高了基础细胞内cAMP水平。我们早期的报告表明，GPR3增强神经突起生长和神经元存活。然而，GPR3在神经元损伤后轴突再生中的潜在作用尚未阐明。在此，我们研究了视网膜GPR3表达及其可能参与小鼠视网膜损伤后轴突再生。GPR3在视网膜神经节细胞（RGC）中相对高表达。令人惊讶的是，GPR3敲除小鼠中的RGC在衰老过程中容易发生神经死亡，而不会影响高眼内压（IOP）和缺血条件。原代培养的视网膜神经元显示，GPR3的表达与轴突生长和神经元存活相关。使用GPR3基因敲除小鼠评估GPR3对轴突再生的影响，揭示了在酵母多糖刺激下，RGCs中的GPR3参与视神经挤压（ONC）后的轴突再生。此外，当GPR3在RGCs中上调时，再生轴突被进一步刺激，并且当与酵母多糖治疗组合时，该效果进一步增强。这些结果表明，GPR3在RGCs中的表达有助于维持小鼠ONC后神经元的存活并加速轴突再生。
Glaucoma is an optic neuropathy and is currently one of the most common diseases that leads to irreversible blindness. The axonal degeneration that occurs before retinal ganglion neuronal loss is suggested to be involved in the pathogenesis of glaucoma. G proteincoupled receptor 3 (GPR3) belongs to the class A rhodopsin-type GPCR family and is highly expressed in various neurons. GPR3 is unique in its ability to constitutively activate the Gαs protein without a ligand, which elevates the basal intracellular cAMP level. Our earlier reports suggested that GPR3 enhances both neurite outgrowth and neuronal survival. However, the potential role of GPR3 in axonal regeneration after neuronal injury has not been elucidated. Herein, we investigated retinal GPR3 expression and its possible involvement in axonal regeneration after retinal injury in mice. GPR3 was relatively highly expressed in retinal ganglion cells (RGCs). Surprisingly, RGCs in GPR3 knockout mice were vulnerable to neural death during aging without affecting high intraocular pressure (IOP) and under ischemic conditions. Primary cultured neurons from the retina showed that GPR3 expression was correlated with neurite outgrowth and neuronal survival. Evaluation of the effect of GPR3 on axonal regeneration using GPR3 knockout mice revealed that GPR3 in RGCs participates in axonal regeneration after optic nerve crush (ONC) under zymosan stimulation. In addition, regenerating axons were further stimulated when GPR3 was upregulated in RGCs, and the effect was further augmented when combined with zymosan treatment. These results suggest that GPR3 expression in RGCs helps maintain neuronal survival and accelerates axonal regeneration after ONC in mice.