NACA

NaCa, short for the sodium-calcium exchanger, refers to a membrane transport protein family that mediates the exchange of sodium and calcium ions across the cell membrane. It is also commonly called NCX. The exchanger functions as a calcium extrusion mechanism in many cell types, helping to restore intracellular Ca2+ to baseline after signals that raise cytosolic Ca2+.

The exchanger operates as an electrogenic antiporter that typically exchanges 3 Na+ ions for 1 Ca2+ ion. Under normal conditions, this forward mode removes Ca2+ from the cell in exchange for Na+ influx, contributing to calcium homeostasis and helping to relax muscle cells, particularly cardiac myocytes. The exchanger can also run in reverse mode when the Na+ gradient or membrane potential is altered, causing Ca2+ entry into the cell in exchange for Na+ efflux. The balance between forward and reverse activity depends on the electrochemical gradients of Na+ and Ca2+, as well as the cell’s voltage.

Mammals express several NCX isoforms, notably NCX1 (SLC8A1), NCX2 (SLC8A2), and NCX3 (SLC8A3), with tissue distribution varying by isoform. NCX1 is abundant in the heart and vascular system, where it plays a key role in excitation-contraction coupling and diastolic calcium removal; NCX2 and NCX3 are important in the brain and skeletal muscle.

Regulation of NaCa involves intracellular Na+, Ca2+, and Mg2+ levels, phosphorylation status, and interactions with regulatory proteins. Pharmacological inhibitors and modulators, such as SEA0400, KB-R7943, and SN-6, are used in research to study NCX function but can lack specificity.

Dysfunction or dysregulated NCX activity has been linked to cardiac arrhythmias, ischemia-reperfusion injury, and other calcium-related pathologies.