Na⁺ /H⁺ exchanger-1 (NHE1).  Stoichiometry = 1:1. TMS VI of NHE1 is a discontinuous pore-lining helix with residues Asn(227), Ile(233), and Leu(243) lining the translocation pore (Tzeng et al., 2010). (orthologous to NHE1 of rat, TC# 2.A.36.1.1). Both Pro167 and Pro168 in TMS IV are required for normal NHE activity (Slepkov et al. 2004). NHE1 regulates internal pH in human monocytes and is important in heart disease and cancer (Tsai et al. 2015). Structural studies have been performed using NMR and EPR (Lee et al., 2011; Nygaard et al. 2011).  Extracytoplasmic loops contribute to ion coordination and inhibitor sensitivity (Lee et al. 2012).  The regulation of NHE1 has been reviewed (Wakabayashi et al. 2013).  CD44 (LHR, MDU2, MDU3, MIC4; P16070; TC# 9.B.87.1.31) regulates breast cancer metastasis by regulating NHE1 expression (Chang et al. 2014).  The role of NHE1 in kidney proximal tubule functions, including pH regulation, vectorial Na⁺ transport, cell volume control and cell survival has been reviewed (Parker et al. 2015).  Helix M9 and the adjacent exofacial re-entrant loop 5 between M9 and M10 (EL5) are important elements involved in cation transport and inhibitor sensitivity (Jinadasa et al. 2015).  A 12 TMS topology has been confirmed (Liu et al. 2015).  Mutations  cause Lichtenstein-Knorr syndrome, an autosomal recessive condition that associates sensorineural hearing loss with cerebellar ataxia (Guissart et al. 2015). Cleaved FAS ligand (transmembrane CD95L; 1 TMS; P48023) activates NHE1 through the Akt/ROCK1 signalling pathway to stimulate cell motility (Monet et al. 2016). NHE1 may contribute to internal pH and motility of mammalian sperm (Muzzachi et al. 2018). NHE1 appears to be the only significant regulator of intracellular pH in preimplantation mouse embryos (Siyanov and Baltz 2013). The intracellular loop, IL5, is critical for proton sensing and ion transport (Wong et al. 2018). NHE1 and CD44 (the hyaluronan receptor with 742 aas and 2 TMSs, one at the N-terminus and one at the C-terminus (P16070)) appear to play important roles in cardiac remodeling (Suleiman et al. 2018). A three-dimensional model of NHE1, accounting for inhibitor binding, has been proposed (Dutta and Fliegel 2019). It forms a complex with Kv11.1 (TC# 1.A.1.20.1) and β-integrin (TC# 9.B.87.1.25). Activation of Na⁺/H⁺ exchanger isoform 1 is regulated by the extracellular environment and protein cofactors, including calcineurin B homologous proteins 1 and 2 (Cottle et al. 2020). NHE1, a central regulator of transmembrane pH that supports carcinogenic progression, is inhibited by 5- and 6-substituted amilorides (Buckley et al. 2021). The roles of NHE1 in health and disease have been reviewed (Fliegel 2021). Citronellal suppresses the expression of NHE1 and TPRM2, alleviates oxidative stress-induced mitochondrial damage, and imposes a protective effect on endothelial dysfunction in type 2 diabetes mellitus rats (Yin et al. 2022). Osmotic stress increases the intracellular pH through SLC9A1 (Zhang et al. 2022). Oxaliplatin (OHP)-induced intracellular acidification of dorsal root ganglion (DRG) neurons largely depends on calcineurin (CaN)-mediated NHE1 inhibition, revealing new mechanisms that OHP can exert to alter neuronal excitability (Dionisi et al. 2023). Slc9a1 plays a vital role in chitosan oligosaccharide transport across the intestinal mucosa of mice (Wen et al. 2023).