Regular ArticleLeu143 in the Putative Fourth Membrane Spanning Domain Is Critical for Amiloride Inhibition of an Epithelial Na+/H+ Exchanger Isoform (NHE-2)
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Characterization of modeled inhibitory binding sites on isoform one of the Na<sup>+</sup>/H<sup>+</sup> exchanger
2021, Biochimica et Biophysica Acta - BiomembranesCitation Excerpt :Additionally, changes in amiloride sensitivity can be accompanied by differences in Na+ kinetics however changes in amiloride sensitivity can also occur without changes in Na+ affinity [30,31]. Different resistance between different NHE isoforms is noted despite similar Na+ kinetics and large changes in NHE1 inhibition can be made more resistant by mutation, despite having Na+ transport unaltered [36,45]. Taken together the results suggest a complex relationship between inhibitor binding sites and Na+, they may be distinct and either cooperative or partially overlapping sites.
Molecular characterization, cellular localization, and light-enhanced expression of Beta-Na <sup>+</sup> /H <sup>+</sup> Exchanger-like in the whitish inner mantle of the giant clam, Tridacna squamosa, denote its role in light-enhanced shell formation
2019, GeneCitation Excerpt :This rendered the protein a 30-fold increase in resistance to the amiloride analog, methylpropyl amiloride. Likewise, when Leu143 was mutated to phenylalanine in mammalian NHE2 (L143F), the transporter displayed a 5-fold greater resistant to amiloride than the wild-type NHE2 (Yun et al., 1993). Hence, the retention of NHE1 attributes with its own distinctive regulatory properties in βNHE-like of T. squamosa gives further support to its identity.
Structural dynamics and regulation of the mammalian SLC9A family of Na<sup>+</sup>/H<sup>+</sup> exchangers
2014, Current Topics in MembranesCitation Excerpt :A NHE3-specific inhibitor, S3226 (Ki = 0.02 μM for NHE3, 3.6 μM for NHE1) also exists (Schwark et al., 1998). A number of mutagenesis studies have addressed the mechanisms by which these inhibitors interact with NHE1, in particular, residues in TMIV and TMIX–TMXI appear to be important for the interaction, consistent with the partially competitive nature of NHE inhibition by these compounds (Counillon, Franchi, & Pouyssegur, 1993; Khadilkar, Iannuzzi, & Orlowski, 2001; Orlowski & Kandasamy, 1996; Pedersen, King, Nygaard, Rigor, & Cala, 2007; Touret, Poujeol, & Counillon, 2001; Yun et al., 1993). Very early it was recognized that NHEs encompass a large membrane embedded part with a suggested topology of 10–13 TM segments of helical character (Orlowski, Kandasamy, & Shull, 1992; Rothman, Padan, & Schuldiner, 1996; Sardet, Franchi, & Pouyssegur, 1989; see Wakabayashi, Ikeda, et al., 1997; Wakabayashi, Shigekawa, et al., 1997).
NHE1 inhibition by amiloride- and benzoylguanidine-type compounds: Inhibitor binding loci deduced from chimeras of NHE1 homologues with endogenous differences in inhibitor sensitivity
2007, Journal of Biological ChemistryCitation Excerpt :Previous studies have largely addressed this question based on the identification of point mutations associated with reduced inhibitor sensitivity in the mammalian NHE1. These studies primarily point to regions in TM4 and TM9 as important for inhibitor sensitivity (15, 17, 18, 20–22, 33). In loss-of-function studies, however, it is difficult to distinguish between a direct role of the amino acids in question and global changes resulting in deterioration of protein integrity.
Identification of Sites in the Second Exomembrane Loop and Ninth Transmembrane Helix of the Mammalian Na<sup>+</sup>/H<sup>+</sup> Exchanger Important for Drug Recognition and Cation Translocation
2001, Journal of Biological ChemistryCitation Excerpt :We also corroborated earlier findings that replacement of Leu167 with Phe (present at the equivalent position of NHE3) in M4 also significantly reduced drug sensitivity (30). Indeed, this site seems to be generally important for drug recognition by the NHEs, since mutagenesis of the equivalent residue in rabbit NHE2 (L143F) also reduced its sensitivity to amiloride compounds (44). To further confirm the involvement of transmembrane helices M4 and M9 in drug recognition, we combined the L167F and G356A mutations.