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 PLCδ 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.

Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells

“…Regarding the downstream signaling mechanism, ER stress induces a disturbance of Ca 2+ homeostasis, leading to the accumulation of Ca 2+ in both mitochondria and cytoplasm, exerting deleterious effects [ 44 , 45 ]. Mitochondrial Ca 2+ overload induces ROS overproduction by causing complex II disintegration, resulting in the opening of the mitochondrial permeability transition pore and the release of ROS [ 46 , 47 ]. Weindel et al found that elevated mitochondrial ROS promoted macrophage necroptosis in a RIPK3/MLKL-dependent manner [ 48 ].…”

Signaling Pathway Governed by Lipid Derived Molecules as Secondary Messenger

“…The proapoptoticCa 2+ transport between the ER and the mitochondria has recently been linked to Inositol Triphophate Receptor subtype 3, not Inositol Triphophate Receptor subtype 1, and voltage dependent anion channel 1 in the Mitochondria associated ER membrane (De Stefani et. al., 2012, Oh, 2023. Cell destiny appears to be significantly influenced by the strength of the Ca 2+ signal that mitochondria receive.…”

Piezo1 ion channels are capable of conformational signaling

“…Glogowska and colleagues already demonstrated that TREK1 modulation persists under conditions of zero net ion flow through Piezo1 and in the absence of calcium ions 27 . However, to test our hypothesis we needed to carefully quantify how the extent of modulation varied with ionic species; specifically, we focused on calcium, which regulates many cellular processes, including metabolism of phosphoinositides and other lipids, any of which could modulate TREK1 activity 32,33 .…”