Phosphoinositides and intracellular calcium signaling: novel insights into phosphoinositides and calcium coupling as negative regulators of cellular signaling.

Intracellular calcium (Ca) and phosphoinositides (PIPs) are crucial for regulating cellular activities such as metabolism and cell survival. Cells maintain precise intracellular Ca and PIP levels via the actions of a complex system of Ca channels, transporters, Ca ATPases, and signaling effectors, including specific lipid kinases, phosphatases, and phospholipases. Recent research has shed light on the complex interplay between Ca and PIP signaling, suggesting that elevated intracellular Ca levels negatively regulate PIP signaling by inhibiting the membrane localization of PIP-binding proteins carrying specific domains, such as the pleckstrin homology (PH) and Ca-independent C2 domains. This dysregulation is often associated with cancer and metabolic diseases. PIPs recruit various proteins with PH domains to the plasma membrane in response to growth hormones, which activate signaling pathways regulating metabolism, cell survival, and growth. However, abnormal PIP signaling in cancer cells triggers consistent membrane localization and activation of PIP-binding proteins. In the context of obesity, an excessive intracellular Ca level prevents the membrane localization of the PIP-binding proteins AKT, IRS1, and PLCδ via Ca-PIPs, contributing to insulin resistance and other metabolic diseases. Furthermore, an excessive intracellular Ca level can cause functional defects in subcellular organelles such as the endoplasmic reticulum (ER), lysosomes, and mitochondria, causing metabolic diseases. This review explores how intracellular Ca overload negatively regulates the membrane localization of PIP-binding proteins.