Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine Indianapolis, IN, USA.
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology Seoul, Korea.
Front Cell Neurosci. 2014 May 28;8:135. doi: 10.3389/fncel.2014.00135. eCollection 2014.
Aberrant ion channel function has been heralded as a main underlying mechanism driving epilepsy and its symptoms. However, it has become increasingly clear that treatment strategies targeting voltage-gated sodium or calcium channels merely mask the symptoms of epilepsy without providing disease-modifying benefits. Ion channel function is likely only one important cog in a highly complex machine. Gross morphological changes, such as reactive sprouting and outgrowth, may also play a role in epileptogenesis. Mechanisms responsible for these changes are not well-understood. Here we investigate the potential involvement of the neurite outgrowth-promoting molecule collapsin response mediator protein 2 (CRMP2). CRMP2 activity, in this respect, is regulated by phosphorylation state, where phosphorylation by a variety of kinases, including glycogen synthase kinase 3 β (GSK3β) renders it inactive. Phosphorylation (inactivation) of CRMP2 was decreased at two distinct phases following traumatic brain injury (TBI). While reduced CRMP2 phosphorylation during the early phase was attributed to the inactivation of GSK3β, the sustained decrease in CRMP2 phosphorylation in the late phase appeared to be independent of GSK3β activity. Instead, the reduction in GSK3β-phosphorylated CRMP2 was attributed to a loss of priming by cyclin-dependent kinase 5 (CDK5), which allows for subsequent phosphorylation by GSK3β. Based on the observation that the proportion of active CRMP2 is increased for up to 4 weeks following TBI, it was hypothesized that it may drive neurite outgrowth, and therefore, circuit reorganization during this time. Therefore, a novel small-molecule tool was used to target CRMP2 in an attempt to determine its importance in mossy fiber sprouting following TBI. In this report, we demonstrate novel differential regulation of CRMP2 phosphorylation by GSK3β and CDK5 following TBI.
异常的离子通道功能已被认为是驱动癫痫及其症状的主要潜在机制。然而，越来越明显的是，靶向电压门控钠或钙通道的治疗策略仅仅掩盖了癫痫的症状，而没有提供疾病修饰的益处。离子通道功能可能只是一个高度复杂的机器中的一个重要部件。形态学的巨大变化，如反应性发芽和生长，也可能在癫痫发生中发挥作用。负责这些变化的机制尚不清楚。在这里，我们研究了神经突生长促进分子 collapsin 反应介质蛋白 2（CRMP2）的潜在作用。在这方面，CRMP2 的活性受磷酸化状态调节，多种激酶（包括糖原合酶激酶 3β（GSK3β））磷酸化使其失活。创伤性脑损伤（TBI）后，CRMP2 的磷酸化（失活）在两个不同阶段减少。虽然早期阶段 GSK3β 的失活导致 CRMP2 磷酸化减少，但晚期阶段持续减少的 CRMP2 磷酸化似乎独立于 GSK3β 活性。相反，GSK3β 磷酸化的 CRMP2 减少归因于 cyclin-dependent kinase 5（CDK5）的失活，这允许随后被 GSK3β 磷酸化。基于 TBI 后长达 4 周内活性 CRMP2 比例增加的观察结果，假设它可能驱动神经突生长，因此在这段时间内进行电路重组。因此，使用一种新型小分子工具来靶向 CRMP2，试图确定其在 TBI 后苔藓纤维发芽中的重要性。在本报告中，我们证明了 GSK3β 和 CDK5 对 TBI 后 CRMP2 磷酸化的新的差异调节。
