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p90 RSK activation contributes to cerebral ischemic damage via phosphorylation of Na + /H + exchanger isoform 1
Author(s) -
Manhas Namratta,
Shi Yejie,
Taunton Jack,
Sun Dandan
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06868.x
Subject(s) - mapk/erk pathway , sodium–hydrogen antiporter , phosphorylation , kinase , chemistry , gene isoform , stimulation , extracellular , protein kinase a , ribosomal s6 kinase , ischemia , microbiology and biotechnology , medicine , endocrinology , biochemistry , biology , sodium , protein kinase b , organic chemistry , p70 s6 kinase 1 , gene
J. Neurochem. (2010) 114 , 1476–1486. Abstract Excessive activation of Na + /H + exchanger isoform 1 (NHE‐1) plays a role in cerebral ischemic injury. The current study investigated whether NHE‐1 protein in ischemic brains is regulated by extracellular signal‐regulated kinase (ERK)/90‐kDa ribosomal S6 kinase (p90 RSK ) signaling pathways. A transient focal ischemia in mice was induced by a 60‐min‐occlusion of the middle cerebral artery followed by reperfusion for 3, 10, or 60 min (Rp). Expression of phosphorylated ERK 1/2 was significantly elevated in the ipsilateral hemispheres at 3–10 min Rp and reduced by 60 min Rp. An increase in phosphorylation of p90 RSK , a known NHE‐1 kinase, was also detected at 3–10 min Rp, which was accompanied with a transient elevation of NHE‐1 phosphorylation (p‐NHE‐1). Stimulation of p90 RSK in ischemic neurons was downstream of ERK activation because inhibition of MEK1 (MAP kinase/ERK kinase) with its inhibitor U0126 blocked phosphorylation of p90 RSK . Moreover, direct inhibition of p90 RSK by its selective inhibitor fluoromethyl ketone not only reduced p‐NHE‐1 expression but also ischemic infarct volume. Taken together, our study revealed that reperfusion triggers a transient stimulation of the ERK/p90 RSK pathway. p90 RSK activation contributes to cerebral ischemic damage in part via activation of NHE‐1 protein.