Human RhAG ammonia channel is impaired by the Phe65Ser mutation in overhydrated stomatocytic red cells

Genetet, Sandrine; Ripoche, Pierre; Picot, Julien; Bigot, Sylvain; Delaunay, Jean; Armari‐Alla, Corinne; Colin, Yves; Mouro-Chanteloup, Isabelle

doi:10.1152/ajpcell.00092.2011

Cited by 34 publications

(40 citation statements)

References 52 publications

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“…1c, Stom-deficient: 2.58 ± 0.13 s −1 and Stom-positive: 4.89 ± 0.18 s −1 ). This decrease can be strictly correlated to a diminution of the AE1 activity, since similar expression levels of AE1 were previously demonstrated in Stom-deficient and Stom-positive RBCs12.…”

Section: Resultssupporting

confidence: 79%

“…The identification, as stomatin partners, of the glucose transporter (GLUT1), as well as of anion exchanger 1 (AE1) and water channel aquaporin-1 (AQP1) suggests that stomatin within cholesterol-rich membrane domains plays a role as a membrane-bound scaffolding protein modulating transport proteins. While an interaction with GLUT1 is consistent with the previously demonstrated role of stomatin in regulating the switch from glucose to L-dehydroascorbic acid (DHA) transport in humans and a few other mammals11, our previous study performed on RBCs that express stomatin or not showed that the AQP1-mediated water transport across the membrane was unmodified in stomatin-deficient erythrocytes12. Concerning AE1 activity, to date, no study had demonstrated a role of stomatin in the chloride/bicarbonate exchange.…”

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confidence: 82%

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Stomatin modulates the activity of the Anion Exchanger 1 (AE1, SLC4A1)

Genetet

Desrames

Chouali

et al. 2017

Sci Rep

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Anion Exchanger 1 (AE1) and stomatin are integral proteins of the red blood cell (RBC) membrane. Erythroid and kidney AE1 play a major role in HCO3− and Cl− exchange. Stomatins down-regulate the activity of many channels and transporters. Biochemical studies suggested an interaction of erythroid AE1 with stomatin. Moreover, we previously reported normal AE1 expression level in stomatin-deficient RBCs. Here, the ability of stomatin to modulate AE1-dependent Cl−/HCO3− exchange was evaluated using stopped-flow methods. In HEK293 cells expressing recombinant AE1 and stomatin, the permeabilities associated with AE1 activity were 30% higher in cells overexpressing stomatin, compared to cells with only endogenous stomatin expression. Ghosts from stomatin-deficient RBCs and controls were resealed in the presence of pH- or chloride-sensitive fluorescent probes and submitted to inward HCO3− and outward Cl− gradients. From alkalinization rate constants, we deduced a 47% decreased permeability to HCO3− for stomatin-deficient patients. Similarly, kinetics of Cl− efflux, followed by the probe dequenching, revealed a significant 42% decrease in patients. In situ Proximity Ligation Assays confirmed an interaction of AE1 with stomatin, in both HEK recombinant cells and RBCs. Here we show that stomatin modulates the transport activity of AE1 through a direct protein-protein interaction.

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Section: Resultssupporting

confidence: 79%

supporting

confidence: 82%

Stomatin modulates the activity of the Anion Exchanger 1 (AE1, SLC4A1)

Genetet

Desrames

Chouali

et al. 2017

Sci Rep

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“…The causative gene of this condition is RHAG, encoding the Rh-associated glycoprotein (RhAG) which acts as an ammonia channel (Table 1). 50 Stomatin has been found at low or absent levels in OHS patients, but no mutations have been found in the encoding gene so far. 34 Moreover, a complex syndrome named stomatin-deficient cryohydrocytosis has been described.…”

Section: Overhydrated Hereditary Stomatocytosismentioning

confidence: 99%

New insights on hereditary erythrocyte membrane defects

et al. 2016

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© Ferrata Storti Foundationmary role in the removal of aged RBCs. In order to perform these journeys RBCs must possess and maintain a significant deformability. The main author of this property is certainly the membrane, that ensures both mechanical stability and deformability. After the first proposed model of the RBC membrane skeleton 36 years ago, 1 containing the core elements of the modern model, many additional proteins have been discovered during the intervening decades, and their structures and interactions have been defined. RBC membrane structure has been extensively covered by excellent reviews.2,3 Herein we summarize the main concepts. RBC membrane is composed by a fluid double layer of lipids in which approximately 20 major proteins and at least 850 minor ones are embedded. 4 The membrane is attached to an intracellular cytoskeleton by protein-protein and lipid-protein interactions that confer the erythrocyte shape, stability and deformability. The transmembrane proteins have mainly a transporter function. However, several of these also have a structural function, usually performed by an intracytoplasmic domain interacting with cytoskeletal proteins.The lipid bilayer acts as a barrier for the retention of cations and anions within the red cells, while it allows water molecules to pass through freely. Human erythrocytes have high intracellular K + and low intracellular Na + contents when compared with the corresponding ion concentrations in the plasma. The maintenance of this cation gradient between the cell and its environment involves a passive outward movement of K + , which is pumped back by the action of an ATP-dependent Na + /K + pump in exchange for Na+ ions. This protein belongs to a class of transmembrane proteins with a transport function (Figure 1). The third and more important component of the RBC membrane is the cytoskeleton, a protein network that laminates the inner surface of the membrane. Spectrin aand β-chains, proteins 4.1, or 4.1R, and actin are the main components of this skeleton, maintaining the biconcave shape of the RBC. These components are connected to each other in two protein complexes; ankyrin and protein 4.1 complex. The former is composed by band 3 tetramers, Rh, RhAG, CD47, glycophorin A and protein 4.2. Whereas the protein 4.1 complex is composed by band 3 dimers binding adducins a-and β-, glycophorin C, GLUT1 and stomatin (Figure 1). The ends of spectrin tetramers converge toward a protein 4.1 complex (junctional complex). Electron microscopy (EM) shows that this latter links the tail of six spectrin tetramers, forming a pseudo-hexagonal arrangement. 5Spectrin tetramers include anion transporters (band 3 or chloride/bicarbonate exchange). The capability of these transporters to form aggregates could define the half-life of RBCs, causing antibody binding and removal by the spleen. Defects that interrupt this vertical structure (spectrin-actin interaction) underlie the biochemical and molecular basis of hereditary spherocytosis (HS), whereas defects in horizo...

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“…In both cases, RBCs exhibit a leak to the univalent cations Na + and K + , resulting in altered intracellular cation content and cell volume alterations. Although PIEZO1 and RhAG gene mutations have been identified in xerocytosis [31–33] and the overhydrated form [34], respectively, the molecular basis for both forms of hereditary stomatocytosis is still under investigation.…”

Section: Introductionmentioning

confidence: 99%

Diagnostic tool for red blood cell membrane disorders: Assessment of a new generation ektacytometer

Costa

Suner

Galimand

et al. 2016

Blood Cells, Molecules, and Diseases

107

118

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Inherited red blood cell (RBC) membrane disorders, such as hereditary spherocytosis, elliptocytosis and hereditary ovalocytosis, result from mutations in genes encoding various RBC membrane and skeletal proteins. The RBC membrane, a composite structure composed of a lipid bilayer linked to a spectrin/actin-based membrane skeleton, confers upon the RBC unique features of deformability and mechanical stability. The disease severity is primarily dependent on the extent of membrane surface area loss. RBC membrane disorders can be readily diagnosed by various laboratory approaches that include RBC cytology, flow cytometry, ektacytometry, electrophoresis of RBC membrane proteins and genetics. The reference technique for diagnosis of RBC membrane disorders is the osmotic gradient ektacytometry. However, in spite of its recognition as the reference technique, this technique is rarely used as a routine diagnosis tool for RBC membrane disorders due to its limited availability. This may soon change as a new generation of ektacytometer has been recently engineered. In this review, we describe the workflow of the samples shipped to our Hematology laboratory for RBC membrane disorder analysis and the data obtained for a large cohort of French patients presenting with RBC membrane disorders using a newly available version of the ektacytomer.

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Human RhAG ammonia channel is impaired by the Phe65Ser mutation in overhydrated stomatocytic red cells

Cited by 34 publications

References 52 publications

Stomatin modulates the activity of the Anion Exchanger 1 (AE1, SLC4A1)

Stomatin modulates the activity of the Anion Exchanger 1 (AE1, SLC4A1)

New insights on hereditary erythrocyte membrane defects

Diagnostic tool for red blood cell membrane disorders: Assessment of a new generation ektacytometer

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