SLC8

SLC8, short for solute carrier family 8, designates a group of Na+/Ca2+ exchangers that mediate the exchange of intracellular calcium for extracellular sodium across cell membranes. In humans, the family comprises three genes: SLC8A1 (encoding NCX1), SLC8A2 (NCX2), and SLC8A3 (NCX3).

Expression patterns vary by tissue: NCX1 is widely expressed with a major role in cardiac muscle and vascular smooth muscle; NCX2 is enriched in the brain; NCX3 is found in brain and skeletal muscle.

Mechanism: These exchangers operate with a stoichiometry of 3 Na+ in for 1 Ca2+ out, generating an electrogenic current. The direction of transport depends on transmembrane gradients of Na+ and Ca2+ and the membrane potential. In normal physiology, NCX helps remove cytosolic Ca2+ after contraction (forward mode) and can run in reverse mode under depolarized or high Na+ conditions, potentially bringing Ca2+ into the cytosol.

Structure: NCXs are multi-pass transmembrane proteins, typically with about nine transmembrane segments and a large intracellular cytosolic loop that contains Ca2+-binding regulatory domains (CBD1 and CBD2). The cytosolic loop and adjacent regions mediate regulation by intracellular Na+, Ca2+ and other factors; alternative splicing yields tissue-specific variants.

Physiology and clinical relevance: NCX1 is essential for cardiac excitation-contraction coupling; loss of NCX1 function in mice is lethal. Altered NCX activity has been linked to cardiac arrhythmias, ischemia-reperfusion injury and heart failure. In the nervous system, NCXs contribute to calcium homeostasis and synaptic signaling. Because of their central role in Ca2+ handling, SLC8 family members are studied as potential targets for therapies addressing cardiac and neurovascular disorders.