p90 activation contributes to cerebral ischemic damage via phosphorylation of Na+/H+ exchanger isoform 1.
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.
Manhas
Namratta
N
Department of Neurosurgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53705, USA.
Shi
Yejie
Y
Taunton
Jack
J
Sun
Dandan
D
D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000503:physiopathology*; D004789:Enzyme Activation / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000502:physiology; D015427:Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
D007527:Isoenzymes; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D038744:Ribosomal Protein S6 Kinases, 90-kDa