Wilson, Sarah M. Yeon, Seul Ki Yang, Xiao-Fang Park, Ki Duk Khanna, Rajesh 2024-01-20T09:34:42Z 2024-01-20T09:34:42Z 2022-01-11 2014-05-28 1662-5102 https://pubs.kist.re.kr/handle/201004/126776 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 (GSK3 beta) 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 GSK3 beta, the sustained decrease in CRMP2 phosphorylation in the late phase appeared to be independent of GSK3 beta activity. Instead, the reduction in GSK3 beta-phosphorylated CRMP2 was attributed to a loss of priming by cyclin-dependent kinase 5 (CDK5), which allows for subsequent phosphorylation by GSK3 beta. 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 GSK3 beta and CDK5 following TB I. English FRONTIERS MEDIA SA TEMPORAL-LOBE EPILEPSY GLYCOGEN-SYNTHASE KINASE-3 NATIONAL GENERAL-PRACTICE ANTICONVULSANT LACOSAMIDE EPILEPTIFORM ACTIVITY HIPPOCAMPAL-NEURONS THERAPEUTIC TARGET SIGNALING PATHWAY RHO-KINASE ACTIVATION Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3 beta and CDK5 following traumatic brain injury Article 10.3389/fncel.2014.00135 1 FRONTIERS IN CELLULAR NEUROSCIENCE, v.8 FRONTIERS IN CELLULAR NEUROSCIENCE 8 scie scopus 000336648500001 2-s2.0-84901604890 Neurosciences Neurosciences & Neurology Article TEMPORAL-LOBE EPILEPSY GLYCOGEN-SYNTHASE KINASE-3 NATIONAL GENERAL-PRACTICE ANTICONVULSANT LACOSAMIDE EPILEPTIFORM ACTIVITY HIPPOCAMPAL-NEURONS THERAPEUTIC TARGET SIGNALING PATHWAY RHO-KINASE ACTIVATION CRMP2 GSK3 beta CDK5 phosphorylation mossy fiber sprouting TIMM staining epileptogenesis (S)-Lacosamide