Release and uptake mechanisms of vesicular Ca2+ stores

Abstract

Cells utilize calcium ions (Ca) to signal almost all aspects of cellular life, ranging from cell proliferation to cell death, in a spatially and temporally regulated manner. A key aspect of this regulation is the compartmentalization of Ca in various cytoplasmic organelles that act as intracellular Ca stores. Whereas Ca release from the large-volume Ca stores, such as the endoplasmic reticulum (ER) and Golgi apparatus, are preferred for signal transduction, Ca release from the small-volume individual vesicular stores that are dispersed throughout the cell, such as lysosomes, may be more useful in local regulation, such as membrane fusion and individualized vesicular movements. Conceivably, these two types of Ca stores may be established, maintained or refilled via distinct mechanisms. ER stores are refilled through sustained Ca influx at ER-plasma membrane (PM) membrane contact sites (MCSs). In this review, we discuss the release and refilling mechanisms of intracellular small vesicular Ca stores, with a special focus on lysosomes. Recent imaging studies of Ca release and organelle MCSs suggest that Ca exchange may occur between two types of stores, such that the small stores acquire Ca from the large stores via ER-vesicle MCSs. Hence vesicular stores like lysosomes may be viewed as secondary Ca stores in the cell.

Mechanisms of lysosomal positioning and movement

“…Membrane contact sites are cellular domains where two organelles interact to facilitate molecular function and promote functional integration. As a network, the ER reaches to the farthest corners of the cell and interacts with many organelles including the plasma membrane . In fact, the ER is the largest intracellular organelle and contains the majority of cellular lipids.…”

“…As a network, the ER reaches to the farthest corners of the cell and interacts with many organelles including the plasma membrane. 30,31 In fact, the ER is the largest intracellular organelle and contains the majority of cellular lipids. There is growing evidence that the ER forms membrane contact sites with almost all organelles and the plasma membrane.…”

Role of Protons in Calcium Signaling

“…• TRP channels; many TRP channels can be opened by acids and hence by protons [Numata 2011]; some interesting cases are known [Xu 2015, Vangeel 2019, for example lysosomal TRP channels which can be activated by an inositol 4,5-bisphosphate [Yang 2019].…”

“…The former conveys it to endo/sarcoplasmic reticular stores, the latter takes it outside the cell, exchanging it with a proton [Brini 2011, Hegedűs 2020. The action of the PMCA would acidify the cytosol were it not for the counterbalancing action of the Na + /H + exchangers, which expel the proton in exchange for a Na + ion [Brini 2011, Xu 2015, Yang 2019. The protons are also removed from the cytosol by various kinds of Vacuolar H + -ATPase pump (V-ATPase), which can transport them to the organelles or outside the cell, exchanging them with various cations, including Ca 2+ [Fogarc 2007, Marshansky 2008, Colina-Tenorio 2018.…”

“…This is possible only through the concerted action of the channels, pumps, and exchangers as described. In relation to calcium signaling, it is believed that protons have a mainly regulatory role [Worley 1987, Donoso 1996, Poburko 2011, Raffaello 2016, Yu 2018, Yang 2019. To our knowledge, no study attributes a triggering role to protons or makes an in-depth biochemical investigation of the interdependence mechanism between the H + and Ca 2+ ions.…”