Extracellular acidification activates cAMP responsive element binding protein via Na+/H+ exchanger isoform 1-mediated Ca 2+ oscillation in central nervous system pericytes

Kuniyuki Nakamura, Masahiro Kamouchi, Koichi Arimura, Ataru Nishimura, Junya Kuroda, Koji Ishitsuka, Himiko Tokami, Hiroshi Sugimori, Tetsuro Ago, Takanari Kitazono

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


Objective-We have previously shown that Na+/H+ exchanger isoform 1 (NHE1) plays an important role in Ca2+ signaling and cell proliferation in human central nervous system (CNS) pericytes. The aims of the present study were to elucidate how NHE1-induced Ca2+ signaling during acidosis is transformed into cellular responses in CNS pericytes. Methods and Results-Human CNS pericytes were cultured, and the activation of cAMP responsive element-binding protein (CREB) was evaluated by Western blotting analysis, immunofluorescence, and luciferase assays. In human CNS pericytes, low extracellular Na+ or low pH generated Ca 2+ oscillation and subsequently phosphorylated Ca2+/ calmodulin-dependent kinase II (CaMKII) and CREB in a time-dependent manner. Focal cerebral ischemia was applied using photothrombotic distal middle cerebral artery occlusion in mice, and the phosphorylation of CREB and the production of interleukin-6 were observed in pericytes migrating into the peri-infarct penumbra during the early phase after ischemic insult. Conclusion-Our results indicate that extracellular acidosis induces Ca2+ oscillation via NHE1, leading to Ca2+/CaMKII-dependent CREB activation in human CNS pericytes. Acidosis may upregulate a variety of proteins, such as interleukin-6, through the NHE1-Ca2+/CaMKII-CREB pathway in brain pericytes and may thus modulate brain ischemic insult.

Original languageEnglish
Pages (from-to)2670-2677
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number11
Publication statusPublished - Nov 2012

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine


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