NaCa2Exchanger

The Na+/Ca2+ exchanger (NCX), sometimes written as NaCa2 exchanger, is a membrane transport protein that uses the inward sodium gradient to extrude calcium from cells. It is widely distributed, with prominent expression in cardiac muscle, neurons, and other excitable or metabolically active tissues.

The exchanger operates bidirectionally. In the canonical forward mode, 3 Na+ ions enter the cell in exchange for 1 Ca2+ ion leaving, making the process electrogenic and contributing to the cell’s inward current. Under conditions such as high intracellular Na+ or strong depolarization, NCX can reverse, bringing Ca2+ into the cell in exchange for Na+ extrusion. This dual capability allows NCX to help shape intracellular Ca2+ transients across varying physiological states.

Physiological roles include calcium extrusion during cardiac relaxation, acting alongside SERCA to regulate cytosolic and SR Ca2+ levels. In neurons and other tissues, NCX participates in shaping Ca2+ signals and influencing cellular excitability, synaptic function, and signaling pathways.

Structure and regulation: The NCX family consists of NCX1, NCX2, and NCX3, encoded by SLC8A1, SLC8A2, and SLC8A3. NCX1 is widespread; NCX2 and NCX3 are enriched in brain and skeletal muscle. The protein typically has about 9 transmembrane segments with a large cytosolic loop containing two Ca2+-binding domains (CBD1 and CBD2) that regulate activity. Transport is modulated by the transmembrane Na+ gradient, membrane potential, and intracellular Ca2+.

Clinical relevance: Altered NCX function is linked to cardiovascular disease, ischemia-reperfusion injury, and arrhythmias. Because of its central role in Ca2+ homeostasis, NCX remains a potential therapeutic target.