FXYD domain-containing ion transport regulator 1 (FXYD1)

FXYD domain-containing ion transport regulator 1 (FXYD1), also known as phospholemman (PLM), is a small single-span transmembrane protein highly expressed in heart, skeletal muscle, and brain. It is a principal regulatory subunit of the Na,K-ATPase, the enzyme responsible for maintaining cellular sodium and potassium gradients, crucial for electrical excitability and muscle contraction. FXYD1 modulates the affinity and activity of Na,K-ATPase for sodium and potassium ions in a tissue-specific and physiological-state-dependent manner. Its function is finely regulated by phosphorylation at conserved serines (Ser63, Ser68) by kinases such as PKA and PKC, leading to conformational changes that alter pump activity and thus ionic homeostasis. While not a direct receptor or enzyme, FXYD1 is a therapeutic target as a modulator of a critical ion transporter implicated in cardiovascular pathology, particularly heart failure, by influencing cardiac contractility and response to hormonal signaling. FXYD1’s dysfunction or altered regulation may contribute to disturbed ion homeostasis in disease states including cardiac arrhythmias and heart failure, and it may also be involved secondarily in cancer and metabolic disease by influencing overall Na,K-ATPase function.

Other names

PhospholemmanPLMSodium/potassium-transporting ATPase subunit FXYD1FXYD domain-containing ion transport regulator 1sodium/potassium-transporting ATPase subunit FXYD1

Allosteric modulation of Na,K-ATPase by direct protein–protein interaction. Regulatory phosphorylation by PKA and PKC alters its activity and its interaction with Na,K-ATPase α subunit.