Faculty, Staff and Student Publications

Language

English

Publication Date

2-18-2026

Journal

Open Biology

DOI

10.1098/rsob.250150

PMID

41702424

Abstract

Anti-apoptotic B-cell lymphoma 2 (BCL-2) controls inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca²+ signalling. As cells typically express all three IP3R isoforms in variable abundances that assemble in hetero-tetrameric channels, the specific effects of BCL-2 on each isoform remain unclear. Here, we employed a reductionist approach using HEK293 cells triple-IP3R knockout reconstituted with a single IP3R isoform to elucidate the impact of BCL-2 on Ca2+ signalling by homo-tetrameric IP3R channels. Co-immunoprecipitation experiments demonstrated that BCL-2 interacts with each IP3R isoform. Live-cell Ca²+ imaging revealed that BCL-2 overexpression suppresses Ca²+ signals evoked by any of the three IP3R isoforms. Moreover, BCL-2 overexpression impaired mitochondrial Ca²+ uptake following IP3R-mediated Ca²+ release, irrespective of the IP3R isoform present. To investigate the effects on single IP3R-channel activity, we performed Ca²+-puff analysis using TIRF microscopy in response to UV-flash photolysis of caged IP3. BCL-2 overexpression reduced the number of Ca²+ puffs across all IP3R isoforms without affecting the amplitude or duration of individual puffs. Thus, BCL-2 acts as a universal inhibitor of all three IP3R isoforms, highlighting its critical role in fine-tuning intracellular Ca2+ dynamics to promote cell survival and its potential as a therapeutic target in cancer via its role in Ca2+ signalling.

Keywords

Humans, Inositol 1, 4, 5-Trisphosphate Receptors, Proto-Oncogene Proteins c-bcl-2, HEK293 Cells, Calcium, Protein Isoforms, Calcium Signaling, Protein Binding, Mitochondria, Apoptosis, Protein Multimerization, BCL-2 proteins, IP3 receptors, calcium signalling, organelles

Published Open-Access

yes

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