The connexin43 C-terminal region mediates neuroprotection during stroke.
Connexin43 plays an important role in neuroprotection in experimental stroke models; reducing the expression of this gap junction protein in astrocytes enhances injury upon middle cerebral artery occlusion (MCAO). Because the C-terminal region of connexin43 isimportant for channel activity, we carried out MCAO stroke experiments in mice expressing a truncated form of connexin43 (Cx43DeltaCT mice). Brain sections were analyzed for infarct volume, astrogliosis, and inflammatory cell invasion 4 days after MCAO. Adult cortices and astrocyte cultures were examined for connexin43 (Cx43) expression by immunohistochemistry and Western blot. Cultured astrocytes were also examined for dye coupling, channel conductance, hemichannel activity, and Ca wave propagation. The Cx43DeltaCT mice exhibit enhanced cerebral injury after stroke. Astrogliosis was reduced and inflammatory cell invasion was increased inthe peri-infarct region in these mice compared with controls; Cx43 expression was also altered. Lastly, cultured astrocytes from Cx43DeltaCT mice were less coupled and displayed alterations in channel gating, hemichannel activity, and Ca wave properties. These results suggest that astrocytic Cx43 contributed to the regulation of cell death after stroke and support the view that the Cx43 C-terminal region is important in protection in cerebral ischemia.
Kozoriz
Michael G
MG
Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Canada.
Bechberger
John F
JF
Bechberger
Geralyn R
GR
Suen
Michael W H
MW
Moreno
Alonso P
AP
Maass
Karen
K
Willecke
Klaus
K
Naus
Christian C
CC
D000818:Animals; D001253:Astrocytes / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D018031:Connexin 43 / Q000737:chemistry* / Q000378:metabolism*; D004553:Electric Conductivity; D017629:Gap Junctions; D005911:Gliosis / Q000473:pathology; D007150:Immunohistochemistry; D015640:Ion Channel Gating; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020521:Stroke / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013329:Structure-Activity Relationship
D018031:Connexin 43; D018696:Neuroprotective Agents; D002118:Calcium