Traditional and emerging roles for the SLC9 Na+/H+ exchangers

  title={Traditional and emerging roles for the SLC9 Na+/H+ exchangers},
  author={Daniel G. Fuster and R. Todd Alexander},
  journal={Pfl{\"u}gers Archiv - European Journal of Physiology},
The SLC9 gene family encodes Na+/H+ exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi, and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [22, 46, 128]. The SLC9 gene family (solute carrier classification of transporters: www… 

The SLC9A-C Mammalian Na+/H+ Exchanger Family: Molecules, Mechanisms, and Physiology.

This review presents and discusses the pioneering original work as well as the current state-of-the-art research on mammalian NHEs, the solute carrier (SLC) 9 family, and provides a comprehensive view of core knowledge and recent insights into each family member.

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

A summary of the structure, function and regulation of expression of the SLC9B subfamily members, focusing primarily on the better-studied SLC8B paralog, NHA2, is presented and the potential of these members as drug targets is reviewed.

Pathophysiology of hepatic Na+/H+ exchange (Review).

The present review described the basic biology of NHEs and highlighted their physiological and pathological effects in the liver.

Prokaryotic Na+/H+ Exchangers—Transport Mechanism and Essential Residues

Several aspects of prokaryotic Na+/H+ exchanger structure and function are reviewed, discussing the similarities and differences between different transporters, with a focus on the CPA and IT exchangers.

Transport proteins NHA1 and NHA2 are essential for survival, but have distinct transport modalities

It is shown that single RNAi knockdowns of either Nha1 or Nha2 reduce survival and in combination are lethal, demonstrating a key role for the CPA2 family in ion homeostasis.

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

The cryo-EM structures of bison NHA2 in detergent and in nanodiscs are reported, and it is proposed that the additional N-terminal helix has evolved as a lipid-mediated remodeling switch for the regulation of N HA2 activity.

Na+/H+ Exchangers Are Required for the Development and Function of Vertebrate Mucociliary Epithelia

A requirement for NHEs in vertebrate mucociliary epithelia is revealed and NHE activity is linked to cilia formation and function in differentiating MCCs and the results provide an entry point for the understanding of the contribution of N HEs to signaling, development, and pathogenesis in the human respiratory tract.

Dissecting the proton transport pathway in electrogenic Na+/H+ antiporters

It is shown that one can switch the antiport activity of the bacterial Na+/H+ antiporter NapA from being electrogenic to electroneutral by the mutation of a single lysine residue (K305).

A Review on the Role of Bicarbonate and Proton Transporters during Sperm Capacitation in Mammals

The involvement of Na+/H+ exchangers (NHE) belonging to the SLC9 family and/or voltage-gated proton channels (HVCN1) in sperm capacitation and the acrosome reaction is discussed.

Structure and elevator mechanism of the mammalian sodium/proton exchanger NHE9

Cryogenic electron microscopy of NHE isoform 9 from Equus caballus reveals the conserved architecture of the NHE ion‐binding site, their elevator‐like structural transitions, the functional implications of autism disease mutations and the role of phosphoinositide lipids to promote homodimerization that, together, have important physiological ramifications.



Diversity of the mammalian sodium/proton exchanger SLC9 gene family

Altered NHE activity has been linked to the pathogenesis of several diseases, including essential hypertension, congenital secretory diarrhea, diabetes, and tissue damage caused by ischemia/reperfusion.

Evolutionary origins of eukaryotic sodium/proton exchangers.

The results link the appearance of NHE on the plasma membrane of animal cells to the use of the Na+/K(+)-ATPase to generate the membrane potential and propose appropriate model organisms in which to study the unique properties of each NHE subclass.

Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions.

Interestingly, organellar NHEs have been related to mental disorders, implying a potential role in the brain, thus expanding the physiological significance of these transporters.

Renal expression of novel Na+/H+ exchanger isoform NHE8.

NHE8 is expressed in the proximal tubule, where it may contribute to apical membrane ion transport, and is the mammalian ortholog of this ancient invertebrate isoform.

Cloning of a novel human NHEDC1 (Na+/H+ exchanger like domain containing 1) gene expressed specifically in testis

The cloning and characterization of a novel human NHEDC1 (Na+/H+ exchanger like domain containing 1) gene was mapped to human chromosome 4p24, encoding a putative protein of 515 amino acids.

The Epithelial Sodium-Hydrogen Antiporter Na+/H+ Exchanger 3 Accumulates and Is Functional in Recycling Endosomes*

Results indicate that NHE3 is present and active in recycling endosomes, and modulation of vesicular traffic could contribute to the regulation of Na+ reabsorption across epithelia.

Na+/H+ exchanger isoform 6 (NHE6/SLC9A6) is involved in clathrin-dependent endocytosis of transferrin.

Microscopic analysis revealed that, at 2 min after the onset of endocytosis, colocalization of NHE6, clathrin, and transferrin was observed, which suggests that NHE 6 was localized to endocyTotic,Clathrin-coated vesicles.

A human Na+/H+ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension

It is shown that HsNHA2 (Homo sapiens NHA2) resides on the plasma membrane and, in polarized MDCK cells, localizes to the apical domain, and raised the possibility that NHA genes may contribute to sodium–lithium countertransport activity and salt homeostasis in humans.

Immunochemical characterization of Na+/H+exchanger isoform NHE4.

It is concluded that NHE4 is a 65- to 70-kDa protein with a broad tissue distribution that was expressed most abundantly in stomach and in multiple additional epithelial and nonepithelial rat tissues including skeletal muscle, heart, kidney, uterus, and liver.

An overview of inhibitors of Na(+)/H(+) exchanger.