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

Abstract

Intracellular calcium (Ca2+) and phosphoinositides (PIPs) are crucial for regulating cellular activities such as metabolism and cell survival. Cells maintain precise intracellular Ca2+ and PIP levels via the actions of a complex system of Ca2+ channels, transporters, Ca2+ ATPases, and signaling effectors, including specific lipid kinases, phosphatases, and phospholipases. Recent research has shed light on the complex interplay between Ca2+ and PIP signaling, suggesting that elevated intracellular Ca2+ levels negatively regulate PIP signaling by inhibiting the membrane localization of PIP-binding proteins carrying specific domains, such as the pleckstrin homology (PH) and Ca2+-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 Ca2+ level prevents the membrane localization of the PIP-binding proteins AKT, IRS1, and PLC & delta; via Ca2+-PIPs, contributing to insulin resistance and other metabolic diseases. Furthermore, an excessive intracellular Ca2+ 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 Ca2+ overload negatively regulates the membrane localization of PIP-binding proteins. Metabolic disease: interactions between calcium and lipid-binding proteinsThe intersection between two major signaling mechanisms involving calcium and phospholipids may contribute to chronic medical conditions, including diabetes and cardiovascular disease. Many cellular functions are coordinated by a family of phospholipids known as phosphoinositides (PIP), which selectively recruit certain signaling proteins to the cell membrane for activation. This process is directly involved in modulating metabolic activity. Byung-Chul Oh, Gachon College of Medicine, Incheon, South Korea, reviews how PIP-based signaling is influenced by disturbances in a second pathway regulating calcium ion flux. After reviewing the two signaling pathways, the author notes that abnormally elevated calcium ion levels in cells generate a stress response that can contribute to obesity and diabetes. Oh highlights evidence that this increased calcium creates conditions that actively impede the recruitment of PIP-binding proteins to the cell membrane, further fueling cardiovascular and metabolic dysfunction.