title: Bicarbonate homeostasis in excitable tissues: role of AE3 Cl-/HCO3- exchanger and carbonic anhydrase XIV interaction.
abstract: Bicarbonate transport and metabolism are key elements of normal cellular function. Two alternate transcripts of anion exchanger 3 (AE3), full-length (AE3fl) and cardiac (AE3c), are expressed in central nervous system (CNS), where AE3 catalyzes electroneutral Cl(-)/HCO(3)(-) exchange across the plasma membrane of neuronal and glial cells of CNS. Anion exchanger isoforms, AE3fl and AE3c, associate with the carbonic anhydrases (CA) CAII and CAIV, forming a HCO(3)(-) transport metabolon, to maximize HCO(3)(-) flux across the plasma membrane. CAXIV, with catalytic domain anchored to the extracellular surface, is also expressed in CNS. Here physical association of AE3 and CAXIV was examined by coimmunoprecipitation experiments, using mouse brain and retinal lysates. CAXIV immunoprecipitated with anti-AE3 antibody, and both AE3 isoforms were immunoprecipitated using anti-CAXIV antibody, indicating CAXIV and AE3 interaction in the CNS. Confocal images revealed colocalization of CAXIV and AE3 in Müller and horizontal cells, in the mouse retina. Cl(-)/HCO(3)(-) exchange activity of AE3fl was investigated in transiently transfected human embryonic kidney 293 cells, using intracellular fluorescence measurements of BCECF, to monitor intracellular pH. CAXIV increased the rate of AE3fl-mediated HCO(3)(-) transport by up to 120%, which was suppressed by the CA inhibitor acetazolamide. Association of AE3 and CAXIV may represent a mechanism to enhance disposal of waste CO(2) and to balance pH in excitable tissues.
authors.affiliation: Department of Physiology and Department of Biochemistry, Membrane Protein Research Group, University of Alberta, Edmonton, Canada.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Casey
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
authors.forename: Gul N
authors.initials: GN
authors.lastname: Shah
authors.forename: Bernardo V
authors.initials: BV
authors.lastname: Alvarez
mesh_terms: D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000378:metabolism*; D002460:Cell Line; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism*
chemical_list: D017920:Antiporters; D001639:Bicarbonates; C062002:Slc4a3 protein, mouse; D002245:Carbon Dioxide; D002256:Carbonic Anhydrases; C466621:carbonic anhydrase XIV
references.citation: J Cell Biol. 1993 Apr;121(1):37-48
references.pmid: 8458871
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7608-13
references.pmid: 9636197
references.citation: Neuroscience. 1997 Jul;79(2):591-603
references.pmid: 9200742
references.citation: PLoS One. 2007 Sep 05;2(9):e839
references.pmid: 17786210
references.citation: Proc Natl Acad Sci U S A. 2005 May 31;102(22):8030-5
references.pmid: 15901897
references.citation: Proc Natl Acad Sci U S A. 2007 May 15;104(20):8514-9
references.pmid: 17485676
references.citation: Nat Genet. 2006 Jul;38(7):755-7
references.pmid: 16767101
references.citation: Circ Res. 1995 Dec;77(6):1192-200
references.pmid: 7586232
references.citation: Genomics. 1994 Aug;22(3):605-9
references.pmid: 8001971
references.citation: Biochemistry. 2000 Nov 7;39(44):13344-9
references.pmid: 11063570
references.citation: J Biol Chem. 2001 Dec 21;276(51):47886-94
references.pmid: 11606574
references.citation: J Neurosci. 1994 Oct;14(10):6266-79
references.pmid: 7931579
references.citation: Trends Neurosci. 1992 Oct;15(10):396-402
references.pmid: 1279865
references.citation: Am J Physiol Cell Physiol. 2002 Nov;283(5):C1522-9
references.pmid: 12372813
references.citation: Biochem J. 1999 Nov 15;344 Pt 1:221-9
references.pmid: 10548554
references.citation: Exp Eye Res. 2005 Oct;81(4):492-500
references.pmid: 16126196
references.citation: Biochem J. 2009 Jan 15;417(2):423-39
references.pmid: 19099540
references.citation: Invest Ophthalmol Vis Sci. 2006 Mar;47(3):1185-92
references.pmid: 16505057
references.citation: Epilepsy Res. 2002 Oct;51(3):249-55
references.pmid: 12399075
references.citation: J Physiol. 2004 Aug 15;559(Pt 1):55-65
references.pmid: 15218065
references.citation: Am J Physiol Cell Physiol. 2009 Sep;297(3):C526-36
references.pmid: 19605733
references.citation: Prog Retin Eye Res. 2006 Jul;25(4):397-424
references.pmid: 16839797
references.citation: J Physiol. 1978 Mar;276:233-55
references.pmid: 25957
references.citation: Proc Natl Acad Sci U S A. 1990 Jul;87(14):5278-82
references.pmid: 2371270
references.citation: Mol Membr Biol. 2004 Nov-Dec;21(6):423-33
references.pmid: 15764372
references.citation: Mol Cell Biol. 2006 Jan;26(1):182-91
references.pmid: 16354689
references.citation: Biochemistry. 2003 Oct 28;42(42):12321-9
references.pmid: 14567693
references.citation: Physiol Rev. 2003 Oct;83(4):1183-221
references.pmid: 14506304
references.citation: Oncogene. 1994 Oct;9(10):2877-88
references.pmid: 8084592
references.citation: Physiol Rev. 1981 Apr;61(2):296-434
references.pmid: 7012859
references.citation: J Histochem Cytochem. 2006 Dec;54(12):1379-91
references.pmid: 16924128
references.citation: J Biol Chem. 1998 Oct 23;273(43):28430-7
references.pmid: 9774471
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1918-23
references.pmid: 11172051
references.citation: J Physiol. 1999 May 15;517 ( Pt 1):159-80
references.pmid: 10226157
references.citation: Am J Physiol. 1990 Jun;258(6 Pt 1):C967-81
references.pmid: 2193525
references.citation: J Neurosci. 2009 Mar 11;29(10):3252-8
references.pmid: 19279262
references.citation: J Biol Chem. 2002 Jul 12;277(28):25239-46
references.pmid: 11994299
references.citation: J Physiol. 2002 Nov 1;544(3):679-85
references.pmid: 12411514
references.citation: J Enzyme Inhib Med Chem. 2004 Jun;19(3):199-229
references.pmid: 15499993
references.citation: Circ Res. 1993 May;72(5):993-1003
references.pmid: 8386598
references.citation: Am J Physiol Cell Physiol. 2007 Aug;293(2):C738-48
references.pmid: 17652430
references.citation: Circ Res. 1991 Jan;68(1):269-79
references.pmid: 1845855
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16771-6
references.pmid: 16260723
references.citation: Am J Physiol Cell Physiol. 2004 Jun;286(6):C1423-33
references.pmid: 14736710
references.citation: J Enzyme Inhib Med Chem. 2004 Jun;19(3):231-6
references.pmid: 15499994
references.citation: Hum Mol Genet. 2000 Jun 12;9(10):1465-72
references.pmid: 10888596
references.citation: Circ Res. 1994 Oct;75(4):603-14
references.pmid: 7923606
references.citation: Life Sci. 2006 May 22;78(26):3018-26
references.pmid: 16458934
references.citation: EMBO J. 2005 Jul 20;24(14):2499-511
references.pmid: 15990874
references.citation: Biochemistry. 2000 May 9;39(18):5527-33
references.pmid: 10820026
references.citation: Hypertension. 1998 Apr;31(4):961-7
references.pmid: 9535421
references.citation: Cell. 1989 Dec 1;59(5):927-37
references.pmid: 2686841
references.citation: Hum Mol Genet. 2005 Jan 15;14(2):255-65
references.pmid: 15563508
references.citation: J Neurosci. 2000 Sep 15;20(18):6839-48
references.pmid: 10995828