Bcl-2 interaction with the inositol 1,4,5-trisphosphate receptor: Role in Ca2+ signaling and disease

doi:10.1016/j.ceca.2011.05.011

Cell Calcium

Volume 50, Issue 3, September 2011, Pages 234-241

https://doi.org/10.1016/j.ceca.2011.05.011 Get rights and content

Abstract

The Bcl-2 protein, best known for its ability to inhibit apoptosis, interacts with the inositol 1,4,5-trisphosphate receptor (IP₃R) Ca²⁺ channel to regulate IP₃-mediated Ca²⁺ release from the endoplasmic reticulum. This review summarizes the current state of knowledge regarding the interaction of Bcl-2, and also its homologue Bcl-xl, with the IP₃R and how these interactions regulate Ca²⁺ signaling. The dual role of these interactions in promoting prosurvival Ca²⁺ signals, while at the same time inhibiting proapoptotic Ca²⁺ signals, is discussed. Moreover, this review will elucidate the recently recognized importance of the Bcl-2–IP₃R interaction in human disease.

Introduction

The bcl-2 (B cell lymphoma 2) gene was discovered through analysis of a chromosomal translocation, t(14;18), commonly associated with follicular lymphoma [1], [2], [3]. By placing bcl-2 under control of immunoglobulin gene enhancer elements, this translocation produces abnormally high-level expression of Bcl-2, the protein product encoded by the bcl-2 gene. In a closely related malignancy, chronic lymphocytic leukemia (CLL), Bcl-2 is elevated not by a chromosomal translocation but by loss of micro RNAs required to regulate Bcl-2 expression levels [4], [5]. Bcl-2 elevation contributes to the pathogenesis and therapeutic resistance of follicular lymphoma and CLL by inhibiting apoptosis. Therefore, agents that decrease Bcl-2 expression or inhibit its activity are currently under investigation for the treatment of cancer.

Conversely, a bcl-2 gene polymorphism associated with decreased Bcl-2 expression levels has been recently implicated in the pathogenesis of bipolar disorder [6], [7]. This is fascinating, since abnormal Ca²⁺ signaling is a hallmark of this disorder [8] and lithium, used for many years to treat patients with this illness, works at least in part by increasing Bcl-2 levels [8], [9].

The involvement of both increased and decreased levels of Bcl-2 in the pathogenesis of various disease states indicates that Bcl-2 plays a critical role in cellular homeostasis, perhaps even beyond its well-known role in regulating apoptosis. The recent discovery that Bcl-2 interacts with the inositol 1,4,5-trisphosphate receptor (IP₃R) and both positively and negatively regulates IP₃-mediated Ca²⁺ signals has opened a new window into Bcl-2's fundamental mechanism of action, as well as its role in various disease processes. These topics are the subject of this review. Ultimately, an in depth understanding of Bcl-2's role in regulating Ca²⁺ signals may provide novel ways to target Bcl-2 therapeutically for diseases associated with abnormal Bcl-2 expression.

Section snippets

Bcl-2 and its family members

Bcl-2 is the founding member of a large protein family known for its role in cell death regulation. Although this review primarily focuses on Bcl-2–IP₃R interaction, related contributions of other family members to Ca²⁺ homeostasis and signaling will also be discussed. Membership in the Bcl-2 protein family is defined by the presence of domains of sequence homology, or Bcl-2-homology domains (BH domains) [10]. Each Bcl-2 family member is grouped into one of three subfamilies, based its BH

Summary

Ca²⁺ signaling is intimately linked with cell survival. In using Ca²⁺ as a messenger cells tread a tightrope between appropriate activity and catastrophic demise. Bcl-2 and its homologues play a critical part in tuning cellular Ca²⁺ signals to provoke survival, or to guide cells into physiological forms of cell death. Alteration of Bcl-2 expression or function can critically adjust the balance between malignant cell survival and untimely cell loss. Bcl-2 family members interact with cellular Ca

Acknowledgement

CWD receives research support from NIH/NCI grants CA085804 and CA42755. Martin Bootman is supported by BBSRC.

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Citation Excerpt :
Besides passive Ca2+ leak through basal ER Ca2+-leak channels (see Section 2.3), Ca2+ release out of the ER predominantly occurs via the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) [3,13–15] and the ryanodine receptor (RyR) [16–18]. Especially the role of the IP3R and of IP3-induced Ca2+ release has been recognized in both apoptosis [19,20] and autophagy [21,22]. During the last years, it has become increasingly clear that Ca2+ handling by other organelles, and especially by the mitochondria and the lysosomes, plays an important role in the regulation of apoptosis and autophagy.
The endoplasmic reticulum (ER), mitochondria and lysosomes are physically and/or functionally linked, establishing close contact sites between these organelles. As a consequence, Ca²⁺ release events from the ER, the major intracellular Ca²⁺-storage organelle, have an immediate effect on the physiological function of mitochondria and lysosomes. Also, the lysosomes can act as a Ca²⁺ source for Ca²⁺ release into the cytosol, thereby influencing ER-based Ca²⁺ signaling. Given the important role for mitochondria and lysosomes in cell survival, cell death and cell adaptation processes, it has become increasingly clear that Ca²⁺ signals from or towards these organelles impact these processes. In this review, we discuss the most recent insights in the emerging role of Ca²⁺ signaling in cellular survival by controlling basal mitochondrial bioenergetics and by regulating apoptosis, a mitochondrial process, and autophagy, a lysosomal process, in response to cell damage and cell stress.
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ReviewBcl-2 interaction with the inositol 1,4,5-trisphosphate receptor: Role in Ca2+ signaling and disease

Abstract

Introduction

Section snippets

Bcl-2 and its family members

Summary

Acknowledgement

Cell

Blood

Biol. Psychiatry

Clin. Neurosci. Res.

Brain Res. Rev.

Mol. Cell

Cell

Trends Biochem. Sci.

Mol. Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Cell Calcium

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell Calcium

Curr. Biol.

Cell

J. Biol. Chem.

Mol. Cell

Trends Pharmacol. Sci.

Cell Calcium

Blood

Neuroscience

Neuroscience

Brain Res.

Immunity

J. Biol. Chem.

Cell

Eur. Neuropsychopharmacol.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Neurobiol. Dis.

Blood

J. Biol. Chem.

Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation

Science

Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18

Cell

miR-15 and miR-16 induce apoptosis by targeting BCL2

Proc. Natl. Acad. Sci. U.S.A.

Bcl-2 SNP rs956572 associates with disrupted intracellular calcium homeostasis in bipolar I disorder

Bipolar Disord.

The versatility and universality of calcium signalling

Nat. Rev. Mol. Cell Biol.

Mitochondrial Ca2+ as a key regulator of cell life and death

Cell Death Differ.

Regulation of autophagy by the inositol trisphosphate receptor

Cell Death Differ.

IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond

Apoptosis

Calcium signaling: dynamics, homeostasis and remodelling

Nat. Rev. Mol. Cell Biol.

Review
Bcl-2 interaction with the inositol 1,4,5-trisphosphate receptor: Role in Ca²⁺ signaling and disease

Mitochondrial Ca²⁺ as a key regulator of cell life and death

IP₃ receptors in cell survival and apoptosis: Ca²⁺ release and beyond