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Bcl-2 upregulates calcium efflux through PMCA and NCX1 to preserve intracellular calcium homeostasis and confer resistance to apoptosis
Author(s)
Lin, Tzu Chien
Lee, Ming Jyun
Nguyen, Ngoc Thang
Hsiao, Shih Chuan
Chen, Ying Chi
Chen, Li Hsien
Chiu, Wen Tai
Date Issued
July 1, 2026
Type
Article
Abstract
Bcl-2 has been shown to regulate intracellular calcium (Ca²⁺) homeostasis, thereby influencing cellular metabolism, survival, and apoptosis. While previous studies have primarily focused on Bcl-2′s role in modulating Ca²⁺ levels within the endoplasmic reticulum and mitochondria, extracellular Ca²⁺ is a major determinant of cellular activation and Ca²⁺ homeostasis. Therefore, it is important to investigate whether Bcl-2 also contributes to the regulation of Ca²⁺ flux across the plasma membrane. A vector control, wild-type Bcl-2, and a Bcl-2 mutant were stably expressed in MDCK (Madin-Darby Canine Kidney) cells that lacked endogenous Bcl-2 expression. Real-time intracellular Ca²⁺ measurements by a single-cell fluorimeter were performed to measure Ca²⁺ release and influx with the ratiometric Ca2+ indicator Fura-2 AM. Our results demonstrate that Bcl-2 enhances store-operated Ca²⁺ entry (SOCE)-mediated Ca²⁺ influx, a key mechanism underlying spontaneous Ca²⁺ oscillations. Furthermore, Bcl-2 upregulates the expression of plasma membrane Ca²⁺ ATPase (PMCA) and Na+-Ca²⁺ exchanger 1 (NCX1), which mediate Ca²⁺ extrusion from the cytosol. Pharmacological inhibition of PMCA with resveratrol (RES) and of NCX1 with ORM-10103 suppressed spontaneous Ca²⁺ oscillations, with PMCA playing a more dominant role than NCX1. Additionally, both RES and ORM-10103 exacerbated thapsigargin-induced Ca²⁺ cytotoxicity. Collectively, our findings reveal that Bcl-2 promotes Ca²⁺ influx to sustain oscillatory signaling and facilitates Ca²⁺ efflux to prevent cytotoxic accumulation, thereby maintaining Ca²⁺ homeostasis. This dual regulatory function provides new insights into Bcl-2–mediated Ca²⁺ signaling and its biological significance in apoptosis inhibition, independent of its interactions with other Bcl-2 family proteins.
Citation
Cell Calcium, 136, 2026