Human SLC4A11 Is a Novel NH3/H+ Co-transporter

Zhang, Wenlin; Ogando, Diego G.; Bonanno, Joseph A.; Obukhov, Alexander G.

doi:10.1074/jbc.m114.627455

Cited by 69 publications

(81 citation statements)

References 41 publications

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“…SLC4A11 contributes to the water ''pump'' as a H þ /OH À transporter and by facilitating a water flux. 2,3 SLC4A11 also transports ammonia, 4,5 which may prevent toxic accumulation of this metabolite. 6 SLC4A11 is the only defective gene found in patients with the rare recessive disease congenital hereditary endothelial dystrophy (CHED), which has onset at birth or early in life.…”

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confidence: 99%

Ophthalmic Nonsteroidal Anti-Inflammatory Drugs as a Therapy for Corneal Dystrophies Caused by SLC4A11 Mutation

Kumari

Casey

2018

Invest. Ophthalmol. Vis. Sci.

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Citation: Alka K, Casey JR. Ophthalmic nonsteroidal anti-inflammatory drugs as a therapy for corneal dystrophies caused by SLC4A11 mutation. Invest Ophthalmol Vis Sci. 2018;59:4258-4267. https://doi.org/ 10.1167/iovs.18-24301 PURPOSE. SLC4A11 is a plasma membrane protein of corneal endothelial cells. Some mutations of the SLC4A11 gene result in SLC4A11 protein misfolding and failure to mature to the plasma membrane. This gives rise to some cases of Fuchs' endothelial corneal dystrophy (FECD) and congenital hereditary endothelial dystrophy (CHED). We screened ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) for their ability to correct SLC4A11 folding defects.METHODS. Five ophthalmic NSAIDs were tested for their therapeutic potential in some genetic corneal dystrophy patients. HEK293 cells expressing CHED and FECD-causing SLC4A11 mutants were grown on 96-well dishes in the absence or presence of NSAIDs. Ability of NSAIDs to correct mutant SLC4A11 cell-surface trafficking was assessed with a bioluminescence resonance energy transfer (BRET) assay and by confocal microscopy. The ability of mutant SLC4A11-expressing cells to mediate water flux (SLC4A11 mediates water flux across the corneal endothelial cell basolateral membrane as part of the endothelial water pump) was measured upon treatment with ophthalmic NSAIDs.RESULTS. BRET-assays revealed significant rescue of SLC4A11 mutants to the cell surface by 4 of 5 NSAIDs tested. The NSAIDs, diclofenac and nepafenac, were effective in moving endoplasmic reticulum-retained missense mutant SLC4A11 to the cell surface, as measured by confocal immunofluorescence. Among intracellular-retained SLC4A11 mutants, 20 of 30 had significant restoration of cell surface abundance upon treatment with diclofenac. Diclofenac restored mutant SLC4A11 water flux activity to the level of wild-type SLC4A11 in some cases.CONCLUSIONS. These results encourage testing diclofenac eye drops as a treatment for corneal dystrophy in patients whose disease is caused by some SLC4A11 missense mutations.

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confidence: 99%

Ophthalmic Nonsteroidal Anti-Inflammatory Drugs as a Therapy for Corneal Dystrophies Caused by SLC4A11 Mutation

Kumari

Casey

2018

Invest. Ophthalmol. Vis. Sci.

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“…In support of a common water and NH 3 permeability pathway, a H ϩ -coupled NH 3 co-transporter (SLC4A11) has been demonstrated to allow for water permeation (33,34).…”

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confidence: 99%

Aquaporin 4 as a NH3 Channel

Assentoft

Kaptan

Schneider

et al. 2016

Journal of Biological Chemistry

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Ammonia is a biologically potent molecule, and the regulation of ammonia levels in the mammalian body is, therefore, strictly controlled. The molecular paths of ammonia permeation across plasma membranes remain ill-defined, but the structural similarity of water and NH 3 has pointed to the aquaporins as putative NH 3 -permeable pores. Accordingly, a range of aquaporins from mammals, plants, fungi, and protozoans demonstrates ammonia permeability. Aquaporin 4 (AQP4) is highly expressed at perivascular glia end-feet in the mammalian brain and may, with this prominent localization at the bloodbrain-interface, participate in the exchange of ammonia, which is required to sustain the glutamate-glutamine cycle. Here we observe that AQP4-expressing Xenopus oocytes display a reflection coefficient <1 for NH 4 Cl at pH 8.0, at which pH an increased amount of the ammonia occurs in the form of NH 3 . Taken together with an NH 4 Cl-mediated intracellular alkalization (or lesser acidification) of AQP4-expressing oocytes, these data suggest that NH 3 is able to permeate the pore of AQP4. Exposure to NH 4 Cl increased the membrane currents to a similar extent in uninjected oocytes and in oocytes expressing AQP4, indicating that the ionic NH 4 ؉ did not permeate AQP4.Molecular dynamics simulations revealed partial pore permeation events of NH 3 but not of NH 4 ؉ and a reduced energy barrier for NH 3 permeation through AQP4 compared with that of a cholesterol-containing lipid bilayer, suggesting AQP4 as a favored transmembrane route for NH 3 . Our data propose that AQP4 belongs to the growing list of NH 3 -permeable water channels.

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“…Moreover, recent studies suggest that human SLC4A11 is not involved in HCO 3 − transport but appears to transport H + (OH − ) in a sodium‐independent fashion (Kao et al ; ; Myers et al ) although some authors have reported H + (OH − ) flux is coupled with Na + (Jalimarada et al ; Ogando et al ). Given that the ion transport characteristics of Slc4a11 have not been fully elucidated and remain controversial (Park et al ; Praetorius et al ; Ogando et al ; Kao et al ; Zhang et al ), we evaluated the function of heterologous expressed mouse Slc4a11 and Slc4a7 in CHO‐K1 cells. Figure A shows that CHO‐K1 cells loaded with the pH‐sensitive fluorescent dye BCECF and expressing the mouse Na + ‐HCO 3 − cotransporter Slc4a7, also known as Nbcn1 and NBC3, mediated a Na + ‐dependent intracellular alkalization (HCO 3 − influx) when a large inward‐directed Na + gradient was introduced to the Na + ‐depleted CHO‐K1 cells [white circles; the Slc4a7 ‐transfected cell data are comparable to a previous study (Yang et al )].…”

Section: Resultsmentioning

confidence: 99%

“…SLC4A11 has the least sequence similarity to the other SLC4 HCO 3 − transporter members and its function remains controversial (Parker et al ). Originally thought to be an electrogenic sodium borate cotransporter (Na + (n)‐B(OH − ) 4− ) or cation (Na + or H + ) permeation pathway (Park et al ), subsequent studies reported that SLC4A11 mediates Na + –OH − cotransport (equivalent to a Na + /H + exchanger) (Jalimarada et al ; Ogando et al ); NH 4 + permeation (Ogando et al ), water flux (Vilas et al ; Soumittra et al ), H + (OH − ) transport (Jalimarada et al ; Kao et al , ; Myers et al ), and/or NH 3 –2H + cotransport (Kao et al ; Zhang et al ). Unlike other SLC4 transporters, SLC4A11 does not transport HCO 3 − (Jalimarada et al ; Ogando et al ; Loganathan et al ).…”

Section: Introductionmentioning

confidence: 99%

Slc4a11disruption causes duct cell loss and impairs NaCl reabsorption in female mouse submandibular glands

et al. 2019

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Slc4a11, a member of the Slc4 HCO3 − transporter family, has a wide tissue distribution. In mouse salivary glands, the expression of Slc4a11 mRNA was more than eightfold greater than the other nine members of the Slc4 gene family. The Slc4a11 protein displayed a diffuse subcellular distribution in both the acinar and duct cells of mouse submandibular glands (SMG). Slc4a11 disruption induced a significant increase in the Na+ and Cl− concentrations of stimulated SMG saliva, whereas it did not affect the fluid secretion rate in response to either β‐adrenergic or cholinergic receptor stimulation. Heterologous expressed mouse Slc4a11 acted as a H+/OH− transporter that was uncoupled of Na+ or Cl− movement, and this activity was blocked by ethyl‐isopropyl amiloride (EIPA) but not 4,4′‐Diisothiocyanato‐2,2′‐stilbenedisulfonic acid (DIDS). Slc4a11 disruption revealed that Slc4a11 does not play a major role in intracellular pH regulation in mouse salivary gland cells. In contrast, NaCl reabsorption was impaired in the SMG saliva of female compared to male Slc4a11 null mice, which correlated with the loss of duct cells and a decrease in expression of the duct‐cell‐specific transcription factor Ascl3. Together, our results suggest that Slc4a11 expression regulates the number of ducts cells in the mouse SMG and consequently NaCl reabsorption.

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Human SLC4A11 Is a Novel NH3/H+ Co-transporter

Abstract: Background: Mutations in SLC4A11 result in corneal endothelial dystrophies; however, the transport characteristics of this membrane protein remain unclear. Results: SLC4A11 showed NH 4 Cl-dependent currents indicative of a NH 3 /H ϩ electrogenic co-transport mode.

Cited by 69 publications

References 41 publications

Ophthalmic Nonsteroidal Anti-Inflammatory Drugs as a Therapy for Corneal Dystrophies Caused by SLC4A11 Mutation

Ophthalmic Nonsteroidal Anti-Inflammatory Drugs as a Therapy for Corneal Dystrophies Caused by SLC4A11 Mutation

Aquaporin 4 as a NH3 Channel

Slc4a11disruption causes duct cell loss and impairs NaCl reabsorption in female mouse submandibular glands

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