Crucial roles of calcium ATPases and phosphoinositides: Insights into pathophysiology and therapeutic strategies

Calcium (Ca²⁺) serves as a pivotal intracellular messenger, influencing a diverse array of cellular processes, including muscle contraction, neurotransmission, and hormone secretion. It also plays a critical role in the regulation of gene expression. Intracellular Ca²⁺ levels are stringently controlled and maintained within a narrow physiological range, primarily by plasma membrane Ca²⁺-ATPases, sarco-/endoplasmic reticulum Ca²⁺-ATPases, and secretory pathway Ca²⁺-ATPases. These ATPases orchestrate the influx, efflux, and sequestration of Ca²⁺ across cellular compartments, thereby ensuring cellular functionality and survival. This review delves into the intricate interplay between Ca²⁺ and phosphoinositides, essential lipid signaling molecules that modulate Ca²⁺-ATPase activities and link Ca²⁺ signaling to a wide range of cellular functions. By examining the molecular dynamics of Ca²⁺-ATPases and their regulatory interactions with phosphoinositides, we discuss their roles under both physiological and pathological conditions, highlighting how disturbances in these interactions contribute to disease. Furthermore, we explore the potential of targeting these Ca²⁺ regulatory mechanisms as a therapeutic strategy for diseases characterized by Ca²⁺ dysregulation, providing insights into future research directions and clinical applications.