Anion exchangers in flux: functional differences between human and mouse SLC26A6 polypeptides.
The SLC26 anion transporter polypeptides exhibit considerably greater sequence diversity among near-species orthologues than is found among the SLC4 bicarbonate transporters, and among SLC26 transporters is most marked among SLC26A6 orthologues. This observation prompted systematic functional comparison in Xenopus oocytes of mouse Slc26a6 with several human SLC26A6 polypeptide variants. Mouse and human polypeptides exhibited similar rates of bidirectional [14C]oxalate flux, Cl-/HCO3- exchange, and Cl-/OH- exchange, and similar cAMP-stimulation and enhancement of that stimulation by wild-type but not delta F508 CFTR. However, high rates of 36Cl- and 35S-sulfate transport by mouse Slc26a6 contrasted with low transport rates of the human proteins. The high 36Cl- transport phenotype cosegregated with the transmembrane domain of mouse Slc26a6 in chimera studies. Mouse Slc26a6 and human SLC26A6 each mediated electroneutral Cl-/HCO3- and Cl-/OH- exchange. But, whereas Cl-/oxalate exchange by mouse Slc26a6 was electrogenic, that mediated by human SLC26A6 appeared electroneutral. Oocyte expression of either mouse or human orthologue elicited currents that were pharmacologically distinct from the monovalent anion exchange activities measured in the same lots of oocytes. The human SLC26A6 polypeptide variants SLC26A6c and SLC26A6d were inactive in isotopic flux assays. Understanding of SLC26 transport mechanisms and pathophysiology will benefit from recognition of substantial differences in transport properties among orthologues.
Alper
Seth L
SL
Molecular and Vascular Medicine and Renal Units, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Stewart
Andrew K
AK
Chernova
Marina N
MN
Zolotarev
Alexander S
AS
Clark
Jeffrey S
JS
Vandorpe
David H
DH
D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D010070:Oxalates / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D000076988:Sulfate Transporters; D013431:Sulfates / Q000378:metabolism
D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D026901:Membrane Transport Proteins; D010070:Oxalates; D010455:Peptides; C439529:SLC26A6 protein, human; C466900:Slc26a6 protein, mouse; D000076988:Sulfate Transporters; D013431:Sulfates