Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ß and CDK5 following traumatic brain injury
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-mod...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-05-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00135/full |
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| author | Sarah Marie Wilson Seul eKi Yeon Xiao-Fang eYang Ki Duk ePark Rajesh eKhanna |
| author_facet | Sarah Marie Wilson Seul eKi Yeon Xiao-Fang eYang Ki Duk ePark Rajesh eKhanna |
| author_sort | Sarah Marie Wilson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T13:54:40Z |
| format | Article |
| id | doaj.art-326a07888b0148038d65abd5e69ec106 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-17T13:54:40Z |
| publishDate | 2014-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-326a07888b0148038d65abd5e69ec1062022-12-21T21:45:57ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022014-05-01810.3389/fncel.2014.0013589142Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ß and CDK5 following traumatic brain injurySarah Marie Wilson0Seul eKi Yeon1Xiao-Fang eYang2Ki Duk ePark3Rajesh eKhanna4Indiana University School of MedicineCenter for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology,University of ArizonaCenter for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology,University of ArizonaAberrant 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.http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00135/fullPhosphorylationEpileptogenesismossy fiber sproutingCDK5CRMP2GSK3β |
| spellingShingle | Sarah Marie Wilson Seul eKi Yeon Xiao-Fang eYang Ki Duk ePark Rajesh eKhanna Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ß and CDK5 following traumatic brain injury Frontiers in Cellular Neuroscience Phosphorylation Epileptogenesis mossy fiber sprouting CDK5 CRMP2 GSK3β |
| title | Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ß and CDK5 following traumatic brain injury |
| title_full | Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ß and CDK5 following traumatic brain injury |
| title_fullStr | Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ß and CDK5 following traumatic brain injury |
| title_full_unstemmed | Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ß and CDK5 following traumatic brain injury |
| title_short | Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ß and CDK5 following traumatic brain injury |
| title_sort | differential regulation of collapsin response mediator protein 2 crmp2 phosphorylation by gsk3 223 and cdk5 following traumatic brain injury |
| topic | Phosphorylation Epileptogenesis mossy fiber sprouting CDK5 CRMP2 GSK3β |
| url | http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00135/full |
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