Hormonal regulation of Na⁺-K⁺-ATPase from the evolutionary perspective

Na⁺-K⁺-ATPase, an α/β heterodimer, is an ancient enzyme that maintains Na⁺ and K⁺ gradients, thus preserving cellular ion homeostasis. In multicellular organisms, this basic housekeeping function is integrated to fulfill the needs of specialized organs and preserve whole-body homeostasis. In vertebrates, Na⁺-K⁺-ATPase is essential for many fundamental physiological processes, such as nerve conduction, muscle contraction, nutrient absorption, and urine excretion. During vertebrate evolution, three key developments contributed to diversification and integration of Na⁺-K⁺-ATPase functions. Generation of novel α- and β-subunits led to formation of multiple Na⁺-K⁺-ATPase isoenyzmes with distinct functional characteristics. Development of a complex endocrine system enabled efficient coordination of diverse Na⁺-K⁺-ATPase functions. Emergence of FXYDs, small transmembrane proteins that regulate Na⁺-K⁺-ATPase, opened new ways to modulate its function. FXYDs are a vertebrate innovation and an important site of hormonal action, suggesting they played an especially prominent role in evolving interaction between Na⁺-K⁺-ATPase and the endocrine system in vertebrates.