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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Characterization of an epilepsy-associated variant of the human Cl^–/HCO exchanger AE3

Membrane Protein Research Group, Department of Physiology, University of Alberta, Edmonton, Canada

Submitted 7 November 2008 ; accepted in final form 11 July 2009

Anion exchanger 3 (AE3), expressed in the brain, heart, and retina, extrudes intracellular HCO in exchange for extracellular Cl^–. The SLC4A3 gene encodes two variants of AE3, brain or full-length AE3 (AE3_fl) and cardiac AE3 (cAE3). Epilepsy is a heterogeneous group of disorders characterized by recurrent unprovoked seizures that affect about 50 million people worldwide. The AE3-A867D allele in humans has been associated with the development of IGE (IGE), which accounts for 30% of all epilepsies. To examine the molecular basis for the association of the A867D allele with IGE, we characterized wild-type (WT) and AE3_fl-A867D in transfected human embryonic kidney (HEK)-293 cells. AE3_fl-A867D had significantly reduced transport activity relative to WT (54 ± 4%, P < 0.01). Differences in expression levels or the degree of protein trafficking to the plasma membrane did not account for the defect of AE3_fl-A867D. Treatment with 8-bromo-cAMP (8-Br-cAMP) increased Cl^–/HCO exchange activity of WT and AE3_fl-A867D to a similar degree, which was abolished by preincubation with the protein kinase A (PKA)-specific inhibitor H89. This indicates that PKA regulates WT and AE3_fl-A867D Cl^–/HCO exchange activity. No difference in Cl^–/HCO exchange activity was found between cultures of mixed populations of neonatal hippocampal cells from WT and slc4a3^–/– mice. We conclude that the A867D allele is a functional (catalytic) mutant of AE3 and that the decreased activity of AE3_fl-A867D may cause changes in cell volume and abnormal intracellular pH. In the brain, these alterations may promote neuron hyperexcitability and the generation of seizures.

protein kinase A; intracellular pH

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]