Upregulation of the GEF-H1 pathway after transient cerebral ischemia.

Exp Neurol 2015 Jan 29;263:306-13. Epub 2014 Oct 29.

Neurochemistry Laboratory of Brain Injury, Shock Trauma & Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, United States. Electronic address:

The microtubule-dependent GEF-H1 pathway controls synaptic re-networking and overall gene expression via regulating cytoskeleton dynamics. Understanding this pathway after ischemia is essential to developing new therapies for neuronal function recovery. However, how the GEF-H1 pathway is regulated following transient cerebral ischemia remains unknown. This study employed a rat model of transient forebrain ischemia to investigate alterations of the GEF-H1 pathway using Western blotting, confocal and electron microscopy, dephosphorylation analysis, and pull-down assay. The GEF-H1 activity was significantly upregulated by: (i) dephosphorylation and (ii) translocation to synaptic membrane and nuclear structures during the early phase of reperfusion. GEF-H1 protein was then downregulated in the brain regions where neurons were destined to undergo delayed neuronal death, but markedly upregulated in neurons that were resistant to the same episode of cerebral ischemia. Consistently, GTP-RhoA, a GEF-H1 substrate, was significantly upregulated after brain ischemia. Electron microscopy further showed that neuronal microtubules were persistently depolymerized in the brain region where GEF-H1 protein was downregulated after brain ischemia. The results demonstrate that the GEF-H1 activity is significantly upregulated in both vulnerable and resistant brain regions in the early phase of reperfusion. However, GEF-H1 protein is downregulated in the vulnerable neurons but upregulated in the ischemic resistant neurons during the recovery phase after ischemia. The initial upregulation of GEF-H1 activity may contribute to excitotoxicity, whereas the late upregulation of GEF-H1 protein may promote neuroplasticity after brain ischemia.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.expneurol.2014.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262550PMC
January 2015
3 Reads

Publication Analysis

Top Keywords

gef-h1 pathway
16
gef-h1 protein
16
protein downregulated
12
gef-h1 activity
12
cerebral ischemia
12
brain ischemia
12
upregulation gef-h1
12
gef-h1
11
ischemia
9
activity upregulated
8
early phase
8
downregulated brain
8
brain regions
8
phase reperfusion
8
reperfusion gef-h1
8
transient cerebral
8
electron microscopy
8
brain
6
pathway
5
upregulated
5

Similar Publications