2.A.19.3.1
The 10 TMS cardiac Ca²⁺:3 Na⁺ antiporter, NCX1 (Ren and Philipson 2013).  The Ca²⁺ sensor (residues 371-508) binds cytoplasmic Ca²⁺ allosterically to activate exchange activity) (Nicoll et al., 2006; Ren et al., 2006) NCX1 forms homodimers (Ren et al., 2008). It is present in mitochondria where it catalyzes Ca²⁺ efflux. TMS packing has been analyzed by Ren et al. (2010). Cytoplasmic Ca²⁺ regulates the dimeric NCX by binding to two adjacent Ca²⁺-binding domains (CBD1 and CBD2) located in the large intracellular loop between transmembrane segments 5 and 6. John et al. (2011) showed that Ca²⁺decreases the distance between the cytoplasmic loops of NCX pairs, thereby activating transport.  Ser110 in TMS2 plays a role in both Na⁺ and Ca²⁺ transport (Ottolia and Philipson 2013). nimodipiine-sensitive NCX1, as well as mitochondrial Ca²⁺ uptake, plays an important role in clearing somatic Ca²⁺ after depolarization-induced Ca²⁺ influx in SCN neurons (Wang et al. 2015). Regulation in suprachiasmatic nucleus neurons has been studied (Cheng et al. 2018).  Genetic knockout and pharmacologic inhibitors of NCX1 attenuate hypoxia-induced pulmonary arterial hypertension (Nagata et al. 2020). The main Na⁺ influx pathway in myocardia in neonates is the NCX transporter (Oshiyama et al. 2022).  Cytosolic Ca²⁺ and Na⁺ allosterically regulate Na⁺/Ca²⁺ exchanger (NCX) proteins to vary the NCX-mediated Ca²⁺ entry/exit rates in diverse mammalian cell types (Giladi et al. 2024).