The sodium/calcium exchangers (NCX) use the extracellular sodium concentration to facilitate the extrusion of calcium out of the cell. Alongside the plasma membrane Ca²⁺-ATPase (PMCA) and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA), as well as the sodium/potassium/calcium exchangers (NKCX, SLC24 family), NCX allow recovery of intracellular calcium back to basal levels after cellular stimulation. When intracellular sodium ion levels rise, for example, following depolarisation, these transporters can operate in the reverse direction to allow calcium influx and sodium efflux, as an electrogenic mechanism. Structural modelling suggests the presence of 9 TM segments, with a large intracellular loop between the fifth and sixth TM segments [1].

Although subtype-selective inhibitors of NCX function are not widely available, 3,4-dichlorobenzamil and CBDMB act as non-selective NCX inhibitors, while SEA0400, KB-R7943, SN6, ORM-10103 [4] and ORM-10962 [5] act to inhibit NCX function with varying degrees of selectivity. BED is a preferential NCX3 inhibitor. It inhibits both modes of NCX3 operation, but only the reverse mode of NCX2 (and with reduced potency compared to NCX3) [7]. YM-244769 inhibits NCX3 preferentially over other isoforms [3,8]. Neurounina-1 stimulates NCX1 and NCX2 activity but not that of NCX3 [6].

* Key recommended reading is highlighted with an asterisk

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Gabellini N. (2004) Transcriptional regulation by cAMP and Ca2+ links the Na+/Ca2+ exchanger 3 to memory and sensory pathways. Mol Neurobiol, 30 (1): 91-116. [PMID:15247490]

* Giladi M, Shor R, Lisnyansky M, Khananshvili D. (2016) Structure-Functional Basis of Ion Transport in Sodium-Calcium Exchanger (NCX) Proteins. Int J Mol Sci, 17 (11). [PMID:27879668]

* Khananshvili D. (2013) The SLC8 gene family of sodium-calcium exchangers (NCX) - structure, function, and regulation in health and disease. Mol Aspects Med, 34 (2-3): 220-35. [PMID:23506867]

Khananshvili D. (2014) Sodium-calcium exchangers (NCX): molecular hallmarks underlying the tissue-specific and systemic functions. Pflugers Arch, 466 (1): 43-60. [PMID:24281864]

Lytton J. (2007) Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport. Biochem J, 406 (3): 365-82. [PMID:17716241]

Quednau BD, Nicoll DA, Philipson KD. (2004) The sodium/calcium exchanger family-SLC8. Pflugers Arch, 447 (5): 543-8. [PMID:12734757]

* Sekler I. (2015) Standing of giants shoulders the story of the mitochondrial Na(+)Ca(2+) exchanger. Biochem Biophys Res Commun, 460 (1): 50-2. [PMID:25998733]

Watanabe Y, Koide Y, Kimura J. (2006) Topics on the Na+/Ca2+ exchanger: pharmacological characterization of Na+/Ca2+ exchanger inhibitors. J Pharmacol Sci, 102 (1): 7-16. [PMID:16990699]

Zhang YH, Hancox JC. (2009) Regulation of cardiac Na+-Ca2+ exchanger activity by protein kinase phosphorylation--still a paradox?. Cell Calcium, 45 (1): 1-10. [PMID:18614228]

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3. Iwamoto T, Kita S. (2006) YM-244769, a novel Na+/Ca2+ exchange inhibitor that preferentially inhibits NCX3, efficiently protects against hypoxia/reoxygenation-induced SH-SY5Y neuronal cell damage. Mol Pharmacol, 70 (6): 2075-83. [PMID:16973719]

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6. Molinaro P, Cantile M, Cuomo O, Secondo A, Pannaccione A, Ambrosino P, Pignataro G, Fiorino F, Severino B, Gatta E et al.. (2013) Neurounina-1, a novel compound that increases Na+/Ca2+ exchanger activity, effectively protects against stroke damage. Mol Pharmacol, 83 (1): 142-56. [PMID:23066092]

7. Secondo A, Pignataro G, Ambrosino P, Pannaccione A, Molinaro P, Boscia F, Cantile M, Cuomo O, Esposito A, Sisalli MJ et al.. (2015) Pharmacological characterization of the newly synthesized 5-amino-N-butyl-2-(4-ethoxyphenoxy)-benzamide hydrochloride (BED) as a potent NCX3 inhibitor that worsens anoxic injury in cortical neurons, organotypic hippocampal cultures, and ischemic brain. ACS Chem Neurosci, 6 (8): 1361-70. [PMID:25942323]

8. Yamashita K, Watanabe Y, Kita S, Iwamoto T, Kimura J. (2016) Inhibitory effect of YM-244769, a novel Na⁺/Ca²⁺ exchanger inhibitor on Na⁺/Ca²⁺ exchange current in guinea pig cardiac ventricular myocytes. Naunyn Schmiedebergs Arch Pharmacol, 389 (11): 1205-1214. [PMID:27480939]

Jules Hancox School of School of Physiology, Pharmacology and Neuroscience University of Bristol Office C39A Biomedical Sciences Building University Walk Bristol BS8 1TD UK