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The Journal of Neuroscience, March 11, 2009, 29(10):3252-3258; doi:10.1523/JNEUROSCI.0036-09.2009

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Cellular/Molecular
Carbonic Anhydrases CA4 and CA14 Both Enhance AE3-Mediated Cl^––HCO Exchange in Hippocampal Neurons

Nataliya Svichar,¹ Abdul Waheed,² William S. Sly,² Jean C. Hennings,³ Christian A. Hübner,³ and Mitchell Chesler¹

¹Department of Neurosurgery, New York University Langone Medical Center, New York, New York 10016, ²Department of Biology and Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, and ³Department of Clinical Chemistry, Friedrich-Schiller-Universität, D-07747 Jena, Germany

Correspondence should be addressed to Dr. Mitchell Chesler, Department of Neurosurgery, New York University Langone Medical Center, 550 First Avenue, New York, NY 10016. Email: mitchell.chesler{at}nyumc.org

Carbonic anhydrase (CA) activity in the brain extracellular space is attributable mainly to isoforms CA4 and CA14. In brain, these enzymes have been studied mostly in the context of buffering activity-dependent extracellular pH transients. Yet evidence from others has suggested that CA4 acts in a complex with anion exchangers (AEs) to facilitate Cl^––HCO exchange in cotransfected cells. To investigate whether CA4 or CA14 plays such a role in hippocampal neurons, we studied NH₄⁺-induced alkalinization of the cytosol, which is mitigated by Cl^– entry and HCO exit. The NH₄⁺-induced alkalinization was enhanced when the extracellular CAs were inhibited by the poorly permeant CA blocker, benzolamide, or by inhibitory antibodies specific for either CA4 or CA14. The NH₄⁺-induced alkalinization was also increased with inhibition of anion exchange by 4,4*-diisothiocyanostilbene-2,2*-disulfonic acid, or by eliminating Cl^– from the medium. No effect of benzolamide was seen under these conditions, in which no Cl^––HCO exchange was possible. Quantitative PCR on RNA from the neuronal cultures indicated that AE3 was the predominant AE isoform. Single-cell PCR also showed that Slc4a3 (AE3) transcripts were abundant in isolated neurons. In hippocampal neurons dissociated from AE3-null mice, the NH₄⁺-induced alkalinization was much larger than that seen in neurons from wild-type mice, suggesting little or no Cl^––HCO exchange in the absence of AE3. Benzolamide had no effect on the NH₄⁺-induced alkalinization in the AE3 knock-out neurons. Our results indicate that CA4 and CA14 both play important roles in the regulation of intracellular pH in hippocampal neurons, by facilitating AE3-mediated Cl^––HCO exchange.

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Received Dec. 17, 2008; revised Feb. 9, 2009; accepted Feb. 12, 2009.

Correspondence should be addressed to Dr. Mitchell Chesler, Department of Neurosurgery, New York University Langone Medical Center, 550 First Avenue, New York, NY 10016. Email: mitchell.chesler{at}nyumc.org

This article has been cited by other articles:

				J. R. Casey, W. S. Sly, G. N. Shah, and B. V. Alvarez Bicarbonate homeostasis in excitable tissues: role of AE3 Cl-/HCOFormula exchanger and carbonic anhydrase XIV interaction Am J Physiol Cell Physiol, November 1, 2009; 297(5): 1091 - 1102. [Abstract] [Full Text] [PDF]

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