Coupling acidic organelles with the ER through Ca²⁺ microdomains at membrane contact sites

Abstract

Acidic organelles such as lysosomes serve as non-canonical Ca(2+) stores. The Ca(2+) mobilising messenger NAADP is thought to trigger local Ca(2+) release from such stores. These events are then amplified by Ca(2+) channels on canonical ER Ca(2+) stores to generate physiologically relevant global Ca(2+) signals. Coupling likely occurs at microdomains formed at membrane contact sites between acidic organelles and the ER. Molecular analyses and computational modelling suggest heterogeneity in the composition of these contacts and predicted Ca(2+) microdomain behaviour. Conversely, acidic organelles might also locally amplify and temper ER-evoked Ca(2+) signals. Ca(2+) microdomains between distinct Ca(2+) stores are thus likely to be integral to the genesis of complex Ca(2+) signals.

Keywords: Acidic Ca(2+) stores; CICR; Ca(2+) microdomain; Computational modelling; Cyclic ADP-ribose; Endoplasmic reticulum; IP(3) receptors; Inositol trisphosphate; Lysosomes; Membrane contact sites; NAADP; Ryanodine receptors; TPCN1; TPCN2; Two-pore channels; Vacuole.