Characterization of Human SLC4A10 as an Electroneutral Na/HCO3 Cotransporter (NBCn2) with Cl– Self-exchange Activity

Parker, Mark D.; Musa‐Aziz, Raif; Rojas, José D.; Choi, Inyeong; Daly, Christopher M.; Boron, Walter F.

doi:10.1074/jbc.m707829200

Cited by 87 publications

(101 citation statements)

References 42 publications

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“…Given our observations with CO 2 , one might ask whether AQP1 also would enhance the flux of a permeant weak acid like butyric acid (33). While confirming that AQP1 increases the ⌬pH S in oocytes exposed to CO 2 ( Fig.…”

Section: Results Phs Transientsmentioning

confidence: 97%

Relative CO ₂ /NH ₃ selectivities of AQP1, AQP4, AQP5, AmtB, and RhAG

Musa‐Aziz

Chen

Pelletier

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The water channel aquaporin 1 (AQP1) and certain Rh-family members are permeable to CO 2 and NH3. Here, we use changes in surface pH (pH S) to assess relative CO2 vs. NH3 permeability of Xenopus oocytes expressing members of the AQP or Rh family. Exposed to CO 2 or NH3, AQP1 oocytes exhibit a greater maximal magnitude of pH S change (⌬pHS) compared with day-matched controls injected with H 2O or with RNA encoding SGLT1, NKCC2, or PepT1. With CO 2, AQP1 oocytes also have faster time constants for pH S relaxation ( pHs). Thus, AQP1, but not the other proteins, conduct CO 2 and NH3. Oocytes expressing rat AQP4, rat AQP5, human RhAG, or the bacterial Rh homolog AmtB also exhibit greater ⌬pH S(CO2) and faster pHs compared with controls. Oocytes expressing AmtB and RhAG, but not AQP4 or AQP5, exhibit greater ⌬pH S(NH3) values. Only AQPs exhibited significant osmotic water permeability (P f). We computed channel-dependent (*) ⌬pHS or Pf by subtracting values for H2O oocytes from those of channelexpressing oocytes. For the ratio ⌬pH S(CO2)*/Pf ‫ء‬ , the sequence was AQP5 > AQP1 Х AQP4. For ⌬pH S(CO2)*/⌬pHS(NH3)*, the sequence was AQP4 Х AQP5 > AQP1 > AmtB > RhAG. Thus, each channel exhibits a characteristic ratio for indices of CO 2 vs. NH3 permeability, demonstrating that, like ion channels, gas channels can exhibit selectivity.gas channel ͉ oocyte ͉ permeability ͉ signal peptide ͉ surface pH measurement G as transport through membranes is of fundamental importance for nutritive transport, photosynthesis, oxidative metabolism, and signaling. For most of the past century, we assumed that gas molecules cross biological membranes merely by diffusing through the lipid phase. This dogma was challenged by 2 observations: (i) Apical membranes of gastric-gland cells have no demonstrable permeability to CO 2 or NH 3 (1). (ii) Heterologous expression of the water channel aquaporin 1 (AQP1) increases the CO 2 permeability of Xenopus oocytes (2). Cooper and Boron (3) and Prasad et al. (4) confirmed and extended this observation. Uehlein (5) showed that an AQP plays a physiological role by enhancing CO 2 uptake by plants. Endeward et al. (6) demonstrated that AQP1 accounts for Ϸ60% of the CO 2 permeability of human red blood cells (RBCs). Molecular dynamics simulations suggest that CO 2 can pass through the 4 aquapores of an AQP1 tetramer (7) and especially through the central pore between the 4 monomers (7). Additional data indicate that AQP1 is permeable to nitric oxide (8), and that-when expressed in Xenopus oocytes (9, 10) or when reconstituted into planar lipid bilayers (11)-AQP1, AQP3, AQP8, AQP9, and the plant aquaporin TIP2;1 are all permeable to NH 3 .The AmtB/MEP/Rh proteins represent a second family of gas channels (12-15). Early work showed that AmtB and MEP transport NH 3 or NH 4 ϩ , thereby playing a nutritive role in archaea, bacteria, and fungi (16,17). The crystal structures of the bacterial AmtB (18-20) and Rh50 (21) and the fungal Amt-1 (22) are consistent with the idea that NH 3 passes through a pore in each m...

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Section: Results Phs Transientsmentioning

confidence: 97%

Relative CO ₂ /NH ₃ selectivities of AQP1, AQP4, AQP5, AmtB, and RhAG

Musa‐Aziz

Chen

Pelletier

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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237

244

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“…While many HCO 3 -transporters have been reported in the mammalian kidney, only NDCBE (encoded by Slc4a8) mediates Na + -and Cl --dependent HCO 3 -transport (30,31). NDCBE promotes the electroneutral exchange of 1 intracellular Cl -ion for 1 Na + and 2 HCO 3 -ions.…”

Section: Figurementioning

confidence: 99%

The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice

Leviel¹,

Hübner²,

Houillier³

et al. 2010

J. Clin. Invest.

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Regulation of sodium balance is a critical factor in the maintenance of euvolemia, and dysregulation of renal sodium excretion results in disorders of altered intravascular volume, such as hypertension. The amiloridesensitive epithelial sodium channel (ENaC) is thought to be the only mechanism for sodium transport in the cortical collecting duct (CCD) of the kidney. However, it has been found that much of the sodium absorption in the CCD is actually amiloride insensitive and sensitive to thiazide diuretics, which also block the Na-Cl cotransporter (NCC) located in the distal convoluted tubule. In this study, we have demonstrated the presence of electroneutral, amiloride-resistant, thiazide-sensitive, transepithelial NaCl absorption in mouse CCDs, which persists even with genetic disruption of ENaC. Furthermore, hydrochlorothiazide (HCTZ) increased excretion of Na + and Cl -in mice devoid of the thiazide target NCC, suggesting that an additional mechanism might account for this effect. Studies on isolated CCDs suggested that the parallel action of the Na + -driven Cl -/HCO 3 -exchanger (NDCBE/SLC4A8) and the Na + -independent Cl -/HCO 3 -exchanger (pendrin/SLC26A4) accounted for the electroneutral thiazide-sensitive sodium transport. Furthermore, genetic ablation of SLC4A8 abolished thiazide-sensitive NaCl transport in the CCD. These studies establish what we believe to be a novel role for NDCBE in mediating substantial Na + reabsorption in the CCD and suggest a role for this transporter in the regulation of fluid homeostasis in mice.

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“…Thus -unlike NDCBE -NBCn2 does not couple the transport of Na + and HCO 3 -across the cell membrane to the net transport of Cl -in the opposite direction. Similar to the GABA transporter GAT1 (Loo et al, 2000), the inclusion of Cl -in transport cycles may be facultative, as -in the absence of extracellular Cl --NBCn2 seems capable of Na NBCn2 is expressed throughout the brain (Chen et al, 2008b;Hübner et al, 2004;Parker et al, 2008b;Wang et al, 2000) and choroid plexus . Consistent with a role for NBCn2 in cerebrospinal fluid secretion, NBCn2-knockout mice have a reduced brain ventricle size (Jacobs et al, 2008).…”

Section: Nbcn2 Molecular Functionmentioning

confidence: 99%