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J. Biol. Chem., Vol. 283, Issue 18, 12146-12153, May 2, 2008

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Activation of Cyclic AMP Signaling in Ae2-deficient Mouse Fibroblasts^*

Pablo Mardones, Juan F. Medina, and Ronald P. J. Oude Elferink¹

From the Academic Medical Center (AMC) Liver Center, Academic Medical Center, University of Amsterdam, 1105 BK, Amsterdam, The Netherlands and the Division of Gene Therapy and Hepatology, University Hospital/School of Medicine/Center for Applied Medical Research, University of Navarra, and Ciberehd, E-31008 Pamplona, Spain

Anion exchanger 2 (AE2, SLC4A2) is a ubiquitously expressed membrane solute carrier that regulates intracellular pH (pH_i) by exchanging cytosolic bicarbonate for extracellular chloride. We used fibroblasts from Ae2-deficient (Ae2_a,b^–/–) mice to study the effects of an alkaline shift in resting intracellular pH (pH_i) on the activation of cAMP signaling and gene expression. Ae2_a,b^–/– fibroblasts show increased pH_i (by 0.22 ± 0.03 unit) compared with wild type cells at extracellular pH (pH_o) 7.4 and 37 °C. This shift in resting pH_i is associated with an up-regulation of bicarbonate-activated soluble adenylyl cyclase expression, increased cAMP production, Creb phosphorylation, inducible cAMP early repressor 1 mRNA expression, and impaired activation of c-Fos transcription by forskolin. These results highlight the importance of bicarbonate transport via Ae2 in maintaining pH_i homeostasis in cultured mouse fibroblasts and unveil the role of cAMP in the cellular response to chronic alkalization, which putatively includes an inducible cAMP early repressor 1-mediated attenuation of phosphorylated Creb activity.

Received for publication, December 31, 2007 , and in revised form, February 1, 2008.

^* This work was supported by Netherlands Organization for Scientific Research Program Grant 912-02-73. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ To whom correspondence should be addressed: AMC Liver Center, Academic Medical Center S1-162, University of Amsterdam, Meibergdreef 69-71, 1105 BK, Amsterdam, The Netherlands. Tel.: 31-20-5663828; Fax: 31-20-5669190; E-mail: r.p.oude-elferink{at}amc.uva.nl.

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