Department of Psychiatry, School of Medicine, and Graduate School of Medical and Dental Sciences, Niigata University, 757 Asahimachi Dori-Ichibancho, Chuo-ku, Niigata, 951-8510, Japan.
Department of Neurochemistry and Molecular Cell Biology, School of Medicine, and Graduate School of Medical and Dental Sciences, Niigata University, 757 Asahimachi Dori-Ichibancho, Chuo-ku, Niigata, 951-8510, Japan.
Mol Brain. 2022 Jul 26;15(1):68. doi: 10.1186/s13041-022-00951-6.
Protein kinases are responsible for protein phosphorylation and are involved in important signal transduction pathways; however, a considerable number of poorly characterized kinases may be involved in neuronal development. Here, we considered cyclin G-associated kinase (GAK) as a candidate regulator of neurite outgrowth and synaptogenesis by examining the effects of the selective GAK inhibitor SGC-GAK-1. SGC-GAK-1 treatment of cultured neurons reduced neurite length and decreased synapse number and phosphorylation of neurofilament 200-kDa subunits relative to the control. In addition, the related kinase inhibitor erlotinib, which has distinct specificity and potency from SGC-GAK-1, had no effect on neurite growth, unlike SGC-GAK-1. These results suggest that GAK may be physiologically involved in normal neuronal development, and that decreased GAK function and the resultant impaired neurite outgrowth and synaptogenesis may be related to neurodevelopmental disorders.
蛋白激酶负责蛋白质磷酸化，参与重要的信号转导途径；然而，相当数量的特征不明显的激酶可能参与神经元发育。在这里，我们考虑将周期蛋白 G 相关激酶 (GAK) 作为神经突生长和突触发生的候选调节剂，通过检查选择性 GAK 抑制剂 SGC-GAK-1 的作用来研究。SGC-GAK-1 处理培养的神经元相对于对照减少神经突长度并减少突触数量和神经丝 200 kDa 亚基的磷酸化。此外，相关的激酶抑制剂厄洛替尼，其与 SGC-GAK-1 具有明显不同的特异性和效力，对神经突生长没有影响，不像 SGC-GAK-1。这些结果表明 GAK 可能在正常神经元发育中具有生理作用，并且 GAK 功能降低以及由此导致的神经突生长和突触发生受损可能与神经发育障碍有关。
