title: Extracellular acidification activates cAMP responsive element binding protein via Na+/H+ exchanger isoform 1-mediated Ca²⁺ oscillation in central nervous system pericytes.
abstract: OBJECTIVE
  We have previously shown that Na(+)/H(+) exchanger isoform 1 (NHE1) plays an important role in Ca(2+) signaling and cell proliferation in human central nervous system (CNS) pericytes. The aims of the present study were to elucidate how NHE1-induced Ca(2+) signaling during acidosis is transformed into cellular responses in CNS pericytes.
  
  
  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 Ca(2+)/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.
  
  
  CONCLUSIONS
  Our results indicate that extracellular acidosis induces Ca(2+) oscillation via NHE1, leading to Ca(2+)/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.
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kuniyuki
authors.initials: K
authors.lastname: Nakamura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kamouchi
authors.forename: Koichi
authors.initials: K
authors.lastname: Arimura
authors.forename: Ataru
authors.initials: A
authors.lastname: Nishimura
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Koji
authors.initials: K
authors.lastname: Ishitsuka
authors.forename: Himiko
authors.initials: H
authors.lastname: Tokami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugimori
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ago
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
mesh_terms: D000138:Acidosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: C115163:CREB1 protein, human; D027682:Cation Transport Proteins; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D015850:Interleukin-6; C490998:SLC9A1 protein, human; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2