Overexpression of the gene product of ocular albinism 1 (GPR143/OA1) but not its mutant forms inhibits neurite outgrowth in PC12?cells
Overexpression of the gene product of ocular albinism 1 (GPR143/OA1) but not its mutant forms inhibits neurite outgrowth in PC12?cells
复制标题
眼白化病 1 (GPR143/OA1) 基因产物的过表达（而非其突变形式）抑制 PC12? 细胞中的神经突生长
DOI：
10.1016/j.jphs.2019.09.002
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发表时间：
2019
影响因子：
3.5
通讯作者：
Goshima Yoshio
中科院分区：
文献类型：
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作者：
Masukawa Daiki;Yamada Kaisei;Goshima Yoshio
轴突生长是一个受外部和/或内部机制调控的复杂分化过程。在外部机制中，G蛋白偶联受体(GPCRs)参与了这一过程，但所涉及的途径还不完全清楚。L-3，4-二羟基苯丙氨酸(L-多巴)本身被认为是惰性的，通过转化为多巴胺来缓解帕金森病。我们提出l-DOPA作为一种神经递质。眼白化病1(OA1)的基因产物GPR143被认为是1-DOPA的受体。OA1是一种X连锁疾病，其特征是所有典型的视觉异常与色素减退和视路错误相关，导致严重的视力下降。然而，这种表型的分子基础仍不清楚。为了研究GPR143的功能，我们研究了神经生长因子对嗜铬细胞瘤(PC12)细胞过表达GPR143的表型效应。小鼠GPR143的过表达抑制了突起的生长，这种作用可被拮抗剂Forl-DOPA的环己酯减轻。此外，G蛋白Gα13的敲除可减弱小鼠GPR143对突起生长的抑制作用。人类野生型(Wt)GPR143也抑制轴突生长，但其突变体不能模仿wt GPR143的作用。我们的结果为轴突引导表型接种白化病提供了一种机制。
Neurite outgrowth is a complex differentiation process regulated by external and/or internal mechanisms. Among external mechanisms, G-protein coupled receptors (GPCRs) have been implicated in this process, but the pathways involved are not fully understood. L-3,4-dihydroxyphenylalanine (l-DOPA) is considered to be inert by itself, and to relieve Parkinson's disease through its conversion to dopamine. We have proposed thatl-DOPA acts as a neurotransmitter. GPR143, the gene product of ocular albinism 1 (OA1), was identified as a receptor forl-DOPA. OA1 is an X-linked disorder characterized by all typical visual anomalies associated with hypopigmentation and optic misrouting, resulting in severe reduction of visual acuity. However, the molecular basis for this phenotype remains unknown. To study the function of GPR143, we investigated the phenotypic effect of overexpression of GPR143 in pheochromocytoma (PC12) cells treated with nerve growth factor. Overexpression of mouse GPR143 inhibited neurite outgrowth, and the effect was mitigated byl-DOPA cyclohexylester, an antagonist forl-DOPA. Furthermore, knockdown of G-protein Gα13 attenuated mouse GPR143 induced inhibition of neurite outgrowth. Human wild-type (wt) GPR143 also inhibited neurite outgrowth, but its mutants did not mimic the effect ofwtGPR143. Our results provide a mechanism for axon guidance phenotype inocular albinism 1.