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p38/SAPK2 controls gap junction closure in astrocytes
Author(s) -
Zvalova Darina,
Cordier Jocelyne,
Mesnil Marc,
Junier MariePierre,
Chneiweiss Hervé
Publication year - 2004
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.10334
Subject(s) - biology , astrocyte , microbiology and biotechnology , p38 mitogen activated protein kinases , gap junction , connexin , phosphorylation , protein kinase c , neuroscience , protein kinase a , central nervous system , intracellular
Abstract Astrocyte gap junction communication (GJC) is thought to contribute to death signal propagation following central nervous system injury, noteworthy in some ischemia/anoxia models. The inhibition of p38/stress‐activated protein kinase 2 (p38/SAPK2) by a pyrimidyl imidazole derivative has been reported to reduce the extent of the lesion area after cerebral ischemia. Therefore, interleukin‐1β (IL‐1β), which contributes to stroke‐induced brain injury and activates p38/SAPK2, and hyperosmolarity induced by sorbitol, a potent stimulus of p38/SAPK2 in non‐neuronal cells, were used to investigate a possible involvement of p38/SAPK2 in GJC modulation in mouse cultured astrocytes. Both stimuli inhibited dye coupling within minutes. The IL‐1β effect was transient, while that of sorbitol lasted up to 90 min. Both stimuli induced a rapid p38/SAPK2 activation, the kinetic of which matched that of induction of dye coupling inhibition. Immunocytochemical studies showed that IL‐1β and sorbitol induced a p38/SAPK2 translocation from the nucleus to the cytoplasm. The pharmacological agent SB203580 specifically blocked p38/SAPK2 activation, cytoplasmic translocation and reversed the IL‐1β and sorbitol‐induced inhibition of GJC. Further characterization of the p38/SAPK2 mode of action on GJC, performed with sorbitol, revealed an increased phosphorylation of protein kinase C (PKC) substrates abolished by both PKC inhibitors and SB203580. Expression and serine phosphorylation of connexin 43, the main component of astrocyte gap junctions, were unchanged, suggesting the existence of additional intracellular signaling mechanisms modulating the channel gating. Altogether, these results demonstrate that p38/SAPK2 is a central mediator of IL‐1β and sorbitol inhibitory actions on GJC and establish PKC among the distal effectors of p38/SAPK2. © 2004 Wiley‐Liss, Inc.