title: Functional assessment of SLC4A11, an integral membrane protein mutated in corneal dystrophies.
abstract: SLC4A11, a member of the SLC4 family of bicarbonate transporters, is a widely expressed integral membrane protein, abundant in kidney and cornea. Mutations of SLC4A11 cause some cases of the blinding corneal dystrophies, congenital hereditary endothelial dystrophy, and Fuchs endothelial corneal dystrophy. These diseases are marked by fluid accumulation in the corneal stroma, secondary to defective fluid reabsorption by the corneal endothelium. The role of SLC4A11 in these corneal dystrophies is not firmly established, as SLC4A11 function remains unclear. To clarify the normal function(s) of SLC4A11, we characterized the protein following expression in the simple, low-background expression system Xenopus laevis oocytes. Since plant and fungal SLC4A11 orthologs transport borate, we measured cell swelling associated with accumulation of solute borate. The plant water/borate transporter NIP5;1 manifested borate transport, whereas human SLC4A11 did not. SLC4A11 supported osmotically driven water accumulation that was electroneutral and Na+independent. Studies in oocytes and HEK293 cells could not detect Na+-coupled HCO3-transport or Cl-/HCO3-exchange by SLC4A11. SLC4A11 mediated electroneutral NH3transport in oocytes. Voltage-dependent OH-or H+movement was not measurable in SLC4A11-expressing oocytes, but SLC4A11-expressing HEK293 cells manifested low-level cytosolic acidification at baseline. In mammalian cells, but not oocytes, OH-/H+conductance may arise when SLC4A11 activates another protein or itself is activated by another protein. These data argue against a role of human SLC4A11 in bicarbonate or borate transport. This work provides additional support for water and ammonia transport by SLC4A11. When expressed in oocytes, SLC4A11 transported NH3, not NH3/H.
authors: Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada.
authors: Sampath K
authors: SK
authors: Loganathan
authors: Abteilung für Allgemeine Zoologie, Fachbereich Biologie, Technische Universtät Kaiserslautern, Kaiserslautern, Germany; and.
authors: Hans-Peter
authors: HP
authors: Schneider
authors: Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina.
authors: Patricio E
authors: PE
authors: Morgan
authors: Abteilung für Allgemeine Zoologie, Fachbereich Biologie, Technische Universtät Kaiserslautern, Kaiserslautern, Germany; and.
authors: Joachim W
authors: JW
authors: Deitmer
authors: Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada; joe.casey@ualberta.ca.
authors: Joseph R
authors: http://orcid.org/0000-0002-9890-5056
authors: JR
authors: Casey
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism; D002460:Cell Line; D003315:Cornea / Q000378:metabolism*; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D017136:Ion Transport / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D009865:Oocytes / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D014867:Water / Q000378:metabolism; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D017920:Antiporters; D001639:Bicarbonates; D008565:Membrane Proteins; C425809:SLC4A11 protein, human; D014867:Water; D012964:Sodium
keywords: SLC4A11; ammonia; corneal dystrophy; endothelial cell; water flux