2.A.19.3.4
Sodium/calcium exchanger 1 (Na⁺/Ca²⁺-exchange protein 1), CNC NCX1 of 973 aas and 12 TMSs in a 6 + 6 TMS arrangement.  The cardiac isoform, CAX1.1, like the archaeal homologues for which high resolution 3-d structures are available (TC#s 2.A.19.5.3 and 2.A.19.8.2), have two aqueous ion permeation channels with cavities that can face the cytoplasm or the external medium (John et al. 2013). It exchanges one Ca²⁺ ion against three to four Na⁺ ions, and thereby contributes to the regulation of cytoplasmic Ca²⁺ levels and Ca²⁺-dependent cellular processes (Komuro et al. 1992; , Van Eylen et al. 2001; Kofuji et al. 1992). It also contributes to Ca²⁺ transport during excitation-contraction coupling in muscle. In a first phase, voltage-gated channels mediate the rapid increase of cytoplasmic Ca²⁺ levels due to release of Ca²⁺ stores from the endoplasmic reticulum. SLC8A1 mediates the export of Ca²⁺ from the cell during the next phase, so that cytoplasmic Ca²⁺ levels rapidly return to baseline. It is also required for normal embryonic heart development and the onset of heart contractions. Both NCX1 and NCX2 play important roles in the motility of the gastric fundus, ileum and distal colon (Nishiyama et al. 2016). An amphipathic α-helix in the NCX1 large intracellular loop controls NCX1 palmitoylation. Thus, NCX1 palmitoylation is governed by a distal secondary structure element rather than by local primary sequence (Plain et al. 2017). The anti-aging gene NM_026333 contributes to proton-induced aging via the NCX1-pathway (Osanai et al. 2018). Dynamic palmitoylation modulates its structure, affinity for lipid-ordered domains, and inhibition by XIP (Gök et al. 2020). Na⁺/Ca²⁺ exchanger, NCX1, and canonical transient receptor potential channel 6 (TRPC6) are recruited by STIM1 to mediate Store-Operated Calcium Entry in primary cortical neurons (Tedeschi et al. 2022). SEA0400 is a potent and selective Na⁺/Ca²⁺ exchanger (NCX) inhibitor (Iwamoto et al. 2004).