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

Abstract

Na+/H+exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+and H+across cellular membranes. They belong to an ancient family of highly evolutionarily conserved proteins, and they play essential physiological roles in all phyla. In this review, we focus on the mammalian Na+/H+exchangers (NHEs), the solute carrier (SLC) 9 family. This family of electroneutral transporters constitutes three branches: SLC9A, -B, and -C. Within these, each isoform exhibits distinct tissue expression profiles, regulation, and physiological roles. Some of these transporters are highly studied, with hundreds of original articles, and some are still only rudimentarily understood. In this review, we present and discuss the pioneering original work as well as the current state-of-the-art research on mammalian NHEs. We aim to provide the reader with a comprehensive view of core knowledge and recent insights into each family member, from gene organization over protein structure and regulation to physiological and pathophysiological roles. Particular attention is given to the integrated physiology of NHEs in the main organ systems. We provide several novel analyses and useful overviews, and we pinpoint main remaining enigmas, which we hope will inspire novel research on these highly versatile proteins.

Pyrazine ring-based Na+/H+ exchanger (NHE) inhibitors potently inhibit cancer cell growth in 3D culture, independent of NHE1

“…This renders inhibition of such transporters, alone or as combination therapy, a promising therapeutic approach, as suggested already decades ago 12 . The Na + /H + exchanger isoform 1 (NHE1, SLC9A1) is a major regulator of intracellular pH (pH i ) and is widely explored as a target in cancer as well as in other diseases (see 9,13 ). and MDA-MB-231 spheroids were grown for 7-9 days.…”

“…The most commonly used pyrazinoylguanidine-type NHE1 inhibitors are 5-(N-ethyl-N-isopropyl) amiloride (EIPA), 5-(N,N-dimethyl) amiloride (DMA) and 5-(N,N-hexamethylene) amiloride (HMA). A second class of inhibitors with higher specificity for NHE1 feature replacement of the pyrazine core with a phenyl ring (benzoylguanidine class), with a variety of substituents at the 2-and 5-positions 13,14 . Widely used benzoylguanidine-type inhibitors are cariporide (HOE642) and eniporide 14,15 .…”

“…Widely used benzoylguanidine-type inhibitors are cariporide (HOE642) and eniporide 14,15 . Both compound classes inhibit NHE1 in part by competition with Na + at the transport site, although other regions also contribute to inhibitor sensitivity 13,16,17 . Except for the pyrazinoylguanidine parent compound amiloride, inhibitors in both compound classes generally exhibit Ki values for NHE1 in the nanomolar range [14][15][16]18 .…”

Amino Acids 563–566 of the Na+/H+ Exchanger Isoform 1 C-Terminal Cytosolic Tail Prevent Protein Degradation and Stabilize Protein Expression and Activity

“…Other isoforms of the protein do not have this sequence, nor does invertebrate NHE1 of Drosophila. A number of regulatory features of Na + /H + exchangers appear to be conserved among the isoforms, but this seems to vary when comparing one isoform to another [2,18]. Running the LIAGER or LIAGERS sequences in the eukaryotic linear motif (ELM) database for functional sites in proteins [19] yielded only a low probability N-terminal motif (ˆM{0,1}[FYLIW][ˆP) that initiates protein degradation.…”

“…Precise amino acids within this region binding ATP have not yet been elucidated. It is also worth note that there are proximal PI(4,5)P2 binding sites that overlap with binding sites for the cytoskeletal linker proteins ezrin, radixin, and moesin (ERM proteins) (reviewed in [18]). The ERM binding sites are located close to amino acids 508-512 and 551-560 [2,23], while the PI(4,5)P2 binding sites are reported at amino acids 513-520 and 556-564 (rat) of NHE1 (equivalent to 509-516 and 552-560, respectively, of human NHE1) [2,24].…”