The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney

Anderegg, Manuel; Albano, Giuseppe; Hanke, Daniela; Deisl, Christine; Uehlinger, Dominik E.; Brandt, Simone; Bhardwaj, Rajesh; Hediger, Matthias A.; Fuster, Daniel

doi:10.1016/j.kint.2020.08.023

Cited by 15 publications

(24 citation statements)

References 65 publications

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“…Based on tissue expression, genome location and phloretin sensitivity, human NHA2 was proposed to be the candidate gene for the Na + (Li + ) countertransport activity associated with the development of essential hypertension and diabetes in humans [9][10][11][12] . Indeed, NHA2 aids in sodium reabsorption in the kidney 13,14 and is a critical component of the with-no-lysine kinase 4-sodium-chloride cotransporter (WNK4-NCC) pathway in the regulation of blood pressure 14 . Furthermore, in vitro and in vivo studies show that NHA2 contributes to β-cell insulin secretion 15 .…”

mentioning

confidence: 99%

Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2

Matsuoka

Fudim

Jung

et al. 2022

Nat Struct Mol Biol

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The Na+/H+ exchanger SLC9B2, also known as NHA2, correlates with the long-sought-after Na+/Li+ exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Despite the functional importance of NHA2, structural information and the molecular basis for its ion-exchange mechanism have been lacking. Here we report the cryo-EM structures of bison NHA2 in detergent and in nanodiscs, at 3.0 and 3.5 Å resolution, respectively. The bison NHA2 structure, together with solid-state membrane-based electrophysiology, establishes the molecular basis for electroneutral ion exchange. NHA2 consists of 14 transmembrane (TM) segments, rather than the 13 TMs previously observed in mammalian Na+/H+ exchangers (NHEs) and related bacterial antiporters. The additional N-terminal helix in NHA2 forms a unique homodimer interface with a large intracellular gap between the protomers, which closes in the presence of phosphoinositol lipids. We propose that the additional N-terminal helix has evolved as a lipid-mediated remodeling switch for the regulation of NHA2 activity.

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confidence: 99%

Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2

Matsuoka

Fudim

Jung

et al. 2022

Nat Struct Mol Biol

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“…6B). Since we observed this phenomenon in yeast cells, which may lack some regulatory mechanisms or protein interactions that regulate the activity of Hs NHA2 in mammalian cells (Anderegg et al, 2021), the first 40-50 amino acids of the protein instead perform an autoinhibitory function in Hs NHA2.…”

Section: Resultsmentioning

confidence: 93%

“…In the kidney, NHA2 localizes to distal convoluted tubules, where it is critical for electrolyte (sodium reabsorption) and blood pressure homeostasis (Fuster et al, 2008; Kondapalli et al, 2017). In 2021, Anderegg et al corroborated the NHA2 role in blood pressure regulation in mice, and identified it as critical for the maintenance of serine-threonine with-no-lysine kinase 4 (WNK4) levels, and thus ultimately for the activity of the Na + /Cl − cotransporter NCC in the distal convoluted tubules of the kidney (Anderegg et al, 2021). Increased NHA2 expression also promotes cyst development in an in vitro model of polycystic kidney disease (Prasad et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2

Velázquez

Průša

Masrati

et al. 2022

Preprint

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The human Na+/H+ antiporter NHA2 (SLC9B2) transports Na+ or Li+ across the plasma membrane in exchange for protons, and is implicated in various pathologies. It is a 537 amino acids protein with an 82 residues long hydrophilic cytoplasmic N-terminus followed by a transmembrane part comprising 14 transmembrane helices. We optimized the functional expression of HsNHA2 in the plasma membrane of a salt-sensitive Saccharomyces cerevisiae strain and characterized a set of mutated or truncated versions of HsNHA2 in terms of their substrate specificity, transport activity, localization and protein stability. We identified a highly conserved proline 246, located in the core of the protein, as being crucial for ion selectivity. The replacement of P246 with serine or threonine resulted in antiporters with altered substrate specificity and increased resistance to the HsNHA2-specific inhibitor phloretin that were not only highly active at an acidic pH of 4.0 (like the native antiporter), but also at neutral pH. We also experimentally confirmed the importance of a putative salt bridge between E215 and R432 for antiporter function and structural integrity. Truncations of the first 50 - 70 residues of the N-terminus doubled the transport activity of HsNHA2, whilst changes in the charge at positions E47, E56, K57, or K58 decreased the antiporter’s transport activity. Thus, the hydrophilic N-terminal part of the protein appears to allosterically autoinhibit its cation transport. Our data also show this in vivo approach to be useful for a rapid screening of SNP’s effect on HsNHA2 activity.

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“…In a pancreatic β–cell line, knockdown of NHA2 did not alter endosomal pH ( Deisl et al, 2013 ). Similarly, endosomal and cytoplasmic pH measurements in NHA2-depleted or overexpressing cells did not show NHA2-dependent alterations in renal cell lines ( Anderegg et al, 2021 ). Rao and colleagues suggested chemiosmotic coupling of NHA2 to the proton motive force generated by the V-type H + -ATPase at the plasma membrane of stably-NHA2-transfected MDCK cells, resulting in a virtual Na + efflux pump ( Kondapalli et al, 2012 ).…”

Section: Slc9b2/nha2mentioning

confidence: 83%

The Less Well-Known Little Brothers: The SLC9B/NHA Sodium Proton Exchanger Subfamily—Structure, Function, Regulation and Potential Drug-Target Approaches

Anderegg

Gyimesi

et al. 2022

Front. Physiol.

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The SLC9 gene family encodes Na+/H+ exchangers (NHEs), a group of membrane transport proteins critically involved in the regulation of cytoplasmic and organellar pH, cell volume, as well as systemic acid-base and volume homeostasis. NHEs of the SLC9A subfamily (NHE 1–9) are well-known for their roles in human physiology and disease. Much less is known about the two members of the SLC9B subfamily, NHA1 and NHA2, which share higher similarity to prokaryotic NHEs than the SLC9A paralogs. NHA2 (also known as SLC9B2) is ubiquitously expressed and has recently been shown to participate in renal blood pressure and electrolyte regulation, insulin secretion and systemic glucose homeostasis. In addition, NHA2 has been proposed to contribute to the pathogenesis of polycystic kidney disease, the most common inherited kidney disease in humans. NHA1 (also known as SLC9B1) is mainly expressed in testis and is important for sperm motility and thus male fertility, but has not been associated with human disease thus far. In this review, we present a summary of the structure, function and regulation of expression of the SLC9B subfamily members, focusing primarily on the better-studied SLC9B paralog, NHA2. Furthermore, we will review the potential of the SLC9B subfamily as drug targets.

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The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney

Abstract: The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney.

Cited by 15 publications

References 65 publications

Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2

Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2

Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2

The Less Well-Known Little Brothers: The SLC9B/NHA Sodium Proton Exchanger Subfamily—Structure, Function, Regulation and Potential Drug-Target Approaches

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The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney

Abstract: The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney.

Cited by 15 publications

References 65 publications

Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2

Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2

Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na+/H+ antiporter NHA2

The Less Well-Known Little Brothers: The SLC9B/NHA Sodium Proton Exchanger Subfamily—Structure, Function, Regulation and Potential Drug-Target Approaches

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Allosteric links between the hydrophilic N-terminus and transmembrane core of human Na⁺/H⁺ antiporter NHA2