Dataset Information

Two-pore channel-2 and inositol trisphosphate receptors coordinate Ca²⁺ signals between lysosomes and the endoplasmic reticulum.

ABSTRACT: Lysosomes and the endoplasmic reticulum (ER) are Ca²⁺ stores mobilized by the second messengers NAADP and IP₃, respectively. Here, we establish Ca²⁺ signals between the two sources as fundamental building blocks that couple local release to global changes in Ca²⁺. Cell-wide Ca²⁺ signals evoked by activation of endogenous NAADP-sensitive channels on lysosomes comprise both local and global components and exhibit a major dependence on ER Ca²⁺ despite their lysosomal origin. Knockout of ER IP₃ receptor channels delays these signals, whereas expression of lysosomal TPC2 channels accelerates them. High-resolution Ca²⁺ imaging reveals elementary events upon TPC2 opening and signals coupled to IP₃ receptors. Biasing TPC2 activation to a Ca²⁺-permeable state sensitizes local Ca²⁺ signals to IP₃. This increases the potency of a physiological agonist to evoke global Ca²⁺ signals and activate a downstream target. Our data provide a conceptual framework to understand how Ca²⁺ release from physically separated stores is coordinated.

SUBMITTER: Yuan Y

PROVIDER: S-EPMC10931537 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Two-pore channel-2 and inositol trisphosphate receptors coordinate Ca2+ signals between lysosomes and the endoplasmic reticulum.

Yuan Yu Y Arige Vikas V Saito Ryo R Mu Qianru Q Brailoiu Gabriela C GC Pereira Gustavo J S GJS Bolsover Stephen R SR Keller Marco M Bracher Franz F Grimm Christian C Brailoiu Eugen E Marchant Jonathan S JS Yule David I DI Patel Sandip S

Cell reports 20231230 1

Lysosomes and the endoplasmic reticulum (ER) are Ca2+ stores mobilized by the second messengers NAADP and IP3, respectively. Here, we establish Ca2+ signals between the two sources as fundamental building blocks that couple local release to global changes in Ca2+. Cell-wide Ca2+ signals evoked by activation of endogenous NAADP-sensitive channels on lysosomes comprise both local and global components and exhibit a major dependence on ER Ca<su ...[more]

PMID: 38160394

Similar Datasets

Project description:AimsPhospholamban (PLB) is the key regulator of the cardiac Ca2+ pump (SERCA2a)-mediated sarcoplasmic reticulum Ca2+ stores. We recently reported that PLB is highly concentrated in the nuclear envelope (NE) from where it can modulate perinuclear Ca2+ handling of the cardiomyocytes (CMs). Since inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) mediates nuclear Ca2+ release, we examined whether the nuclear pool of PLB regulates IP3-induced nuclear Ca2+ handling.Methods and resultsFluo-4 based confocal Ca2+ imaging was performed to measure Ca2+ dynamics across both nucleus and cytosol in saponin-permeabilized CMs isolated from wild-type (WT) or PLB-knockout (PLB-KO) mice. At diastolic intracellular Ca2+ ([Ca2+]i = 100 nM), the Fab fragment of the monoclonal PLB antibody (anti-PLB Fab) facilitated the formation and increased the length of spontaneous Ca2+ waves (SCWs) originating from the nuclear region in CMs from WT but not from PLB-KO mice. We next examined nuclear Ca2+ activities at basal condition and after sequential addition of IP3, anti-PLB Fab, and the IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) at a series of [Ca2+]i. In WT mice, at 10 nM [Ca2+]i where ryanodine receptor (RyR2) based spontaneous Ca2+ sparks rarely occurred, IP3 increased fluorescence amplitude (F/F0) of overall nuclear region to 1.19 ± 0.02. Subsequent addition of anti-PLB Fab significantly decreased F/F0 to 1.09 ± 0.02. At 50 nM [Ca2+]i, anti-PLB Fab not only decreased the overall nuclear F/F0 previously elevated by IP3, but also increased the amplitude and duration of spark-like nuclear Ca2+ release events. These nuclear Ca2+ releases were blocked by 2-APB. At 100 nM [Ca2+]i, IP3 induced short SCWs originating from nucleus. Anti-PLB Fab transformed those short waves into long SCWs with propagation from the nucleus into the cytosol. In contrast, neither nuclear nor cytosolic Ca2+ dynamics was affected by anti-PLB Fab in CMs from PLB-KO mice in all these conditions. Furthermore, in WT CMs pretreated with RyR2 blocker tetracaine, IP3 and anti-PLB Fab still increased the magnitude of nuclear Ca2+ release but failed to regenerate SCWs. Finally, anti-PLB Fab increased low Ca2+ affinity mag-fluo 4 fluorescence intensity in the lumen of NE of nuclei isolated from WT but not in PLB-KO mice.ConclusionPLB regulates nuclear Ca2+ handling. By increasing Ca2+ uptake into lumen of the NE and perhaps other perinuclear membranes, the acute reversal of PLB inhibition decreases global Ca2+ concentration at rest in the nucleoplasm, and increases Ca2+ release into the nucleus, through mechanisms involving IP3R and RyR2 in the vicinity.

Dataset Information

Two-pore channel-2 and inositol trisphosphate receptors coordinate Ca²⁺ signals between lysosomes and the endoplasmic reticulum.

Publications

Two-pore channel-2 and inositol trisphosphate receptors coordinate Ca<sup>2+</sup> signals between lysosomes and the endoplasmic reticulum.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets