Bcl-2-Protein Family as Modulators of IP₃Receptors and Other Organellar Ca²⁺Channels

Abstract

The pro-and antiapoptotic proteins belonging to the B-cell lymphoma-2 (Bcl-2) family exert a critical control over cell-death processes by enabling or counteracting mitochondrial outer membrane permeabilization. Beyond this mitochondrial function, several Bcl-2 family members have emerged as critical modulators of intracellular Ca 2+ homeostasis and dynamics, showing proapoptotic and antiapoptotic functions. Bcl-2 family proteins specifically target several intracellular Ca 2+ -transport systems, including organellar Ca 2+ channels: inositol 1,4,5-trisphosphate receptors (IP 3 Rs) and ryanodine receptors (RyRs), Ca 2+ -release channels mediating Ca 2+ flux from the endoplasmic reticulum, as well as voltage-dependent anion channels (VDACs), which mediate Ca 2+ flux across the mitochondrial outer membrane into the mitochondria. Although the formation of protein complexes between Bcl-2 proteins and these channels has been extensively studied, a major advance during recent years has been elucidating the complex interaction of Bcl-2 proteins with IP 3 Rs. Distinct interaction sites for different Bcl-2 family members were identified in the primary structure of IP 3 Rs. The unique molecular profiles of these Bcl-2 proteins may account for their distinct functional outcomes when bound to IP 3 Rs. Furthermore, Bcl-2 inhibitors used in cancer therapy may affect IP 3 R function as part of their proapoptotic effect and/or as an adverse effect in healthy cells. B-CELL LYMPHOMA-2 (Bcl-2) FAMILY OF PROTEINST he Bcl-2 family of proteins consists of proand antiapoptotic members, which are characterized by the presence of at least one of the four highly conserved α-helical motifs, termed Bcl-2 homology (BH) domains (Adams and Cory 1998). The antiapoptotic family members, such as Bcl-2, Bcl-Xl, and Mcl-1, contain all four BH domains where the BH1, BH2, and BH3 domains form a hydrophobic cleft (Fig. 1A). The hydrophobic cleft is separated from the amino-terminal BH4 domain by an unstructured

Unraveling the Mystery of Cold Stress-Induced Myocardial Injury

“…Under normal physiological conditions, IP3 receptors respond to the needs of the cells under precise regulation in vivo and closely control a variety of Ca-dependent physiological processes. The IP3/Ca 2+ signaling pathway regulates many cellular physiological processes and plays a key role in the development of many diseases (Berridge, 2016;Prole and Taylor, 2019;Ivanova et al, 2020). There are three types of IP3 receptor isoforms, IP3R1, IP3R2, and IP3R3.…”

Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins

“…This regulation can occur through direct interactions between the intracellular Ca 2+ -transport systems and anti-apoptotic Bcl-2 members; in particular Bcl-2, Bcl-XL, Mcl-1, Bax, and Bak [ 255 , 256 , 257 , 258 , 259 , 260 , 261 ]. These members target crucial intracellular Ca 2+ -transport systems such as Ca 2+ -efflux systems of ER/SR (inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs)) and the Ca 2+ -efflux system of mitochondria (involving VDAC, which provides Ca 2+ flux trough OMM, and mPTP, which represents the main Ca 2+ efflux system from mitochondria under pathophysiological conditions) [ 193 , 194 , 211 , 262 ].…”

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“…On the contrary, BCL2 appears to prevent IP3R‐mediated Ca 2+ leakage through the inhibitory binding of its BH4 domain to the regulatory and coupling domain of IP3R . Knowing that BI‐1 interacts directly with BCL2 as well as IP3R adds yet another degree of complexity to understanding cellular [Ca 2+ ] regulation and anti‐apoptotic function (as extensively reviewed in ). While small leakage of Ca 2+ is necessary to avoid overload in the ER, too much ER Ca 2+ depletion disturbs protein production and the Ca 2+ ‐dependent activities of many intraluminal chaperones, suggesting that many actors are certainly at play to fine‐tune [Ca 2+ ] in fundamental organelles and the cell itself.…”