The plasmalemmal sodium pump is the principal consumer of ATP in the body. In cardiac muscle, the pump is essential for normal cardiac function. In skeletal muscle, the sodium pump controls extracellular potassium concentration and therefore membrane potential and muscle fatigue. In the kidney, the ion gradients established by the pump are critical for reabsorption of water and solutes throughout the nephron, and therefore in the control of blood volume, blood pressure and cardiac load.
Regulation of the sodium pump in a variety of tissues is therefore of critical physiological and pathophysiological importance. Functional diversity of pumps in different tissues is achieved in part by tissue-specific expression of an accessory ‘FXYD’ protein, of which 7 different isoforms have been described. S-palmitoylation of FXYD1 causes inhibition of the sodium pump. S-palmitoylation is the reversible covalent post-translational attachment of the fatty acid palmitic acid to the thiol group of cysteine, via an acyl-thioester linkage. In recent years protein S-palmitoylation has emerged as an important and common post-translational modification in a variety of tissues.
All FXYD family members have cysteines in analogous positions to the palmitoylated cysteines in FXYD1, meaning FXYD protein palmitoylation may be a universal means to regulate the pump. This project will systematically define the palmitoylation sites in the remaining 6 FXYD family members, characterise the cellular dynamics of FXYD protein palmitoylation, and investigate the functional consequences of palmitoylation of each FXYD protein for the sodium pump. Hence new mechanisms for regulating the ubiquitous sodium pump will be uncovered.