title: Cyclic AMP and alkaline pH downregulate carbonic anhydrase 2 in mouse fibroblasts.
abstract: BACKGROUND
  The hydration of CO2 catalyzed by the ubiquitous carbonic anhydrase 2 (Ca2) is central for bicarbonate transport, bone metabolism and acid-base homeostasis in metazoans. There is evidence that in some tissues Ca2 expression can be acutely induced by cAMP, whereas in other cell types it is unresponsive to cAMP-mediated transcriptional activation.
  
  
  METHODS
  We isolated fibroblasts from wild type and mice lacking the ubiquitous chloride/bicarbonate exchanger (Ae2a,b(-/-) mice). In these cells the regulation of carbonic anhydrase 2 by cAMP was studied.
  
  
  RESULTS
  We show that Ca2 expression is strongly inhibited by chronic incubation with dibutyryl-cAMP, forskolin or alkaline pH in cultured mouse fibroblasts. Furthermore, fibroblasts obtained from anion exchanger 2 deficient (Ae2a,b(-/-)) mice, which display intracellular alkalosis and increased cAMP production, express less than 10% of control Ca2 mRNA and protein. Surprisingly, inhibition of the bicarbonate-sensitive soluble adenylyl cyclase (sAC) was found to reduce CA2 expression instead of increasing it.
  
  
  CONCLUSIONS
  CA2 expression is strongly regulated by intracellular pH and by cAMP, suggesting a role for soluble adenylyl cyclase. Regulation occurs in opposite directions which may be explained by an incoherent feedforward loop consisting of activation by pCREB and repression by ICER.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Pablo
authors.initials: P
authors.lastname: Mardones
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jung Chin
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: r.p.oude-elferink@amc.uva.nl.
authors.forename: Ronald P J
authors.initials: RP
authors.lastname: Oude Elferink
mesh_terms: D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D024402:Carbonic Anhydrase II / Q000235:genetics*; D002478:Cells, Cultured; D027963:Chloride-Bicarbonate Antiporters / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D015536:Down-Regulation; D005347:Fibroblasts / Q000201:enzymology; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice
chemical_list: D027963:Chloride-Bicarbonate Antiporters; D005576:Colforsin; D000242:Cyclic AMP; D024402:Carbonic Anhydrase II; D000262:Adenylyl Cyclases
keywords: Bicarbonate; Carbonic anhydrase; Chloride/bicarbonate exchanger; Cyclic AMP; Intracellular pH; Soluble adenylyl cyclase