STIM1, but not STIM2, is required for proper agonist-induced Ca2+ signaling

Decuypere, Jean Paul; Monaco, Giovanni; Kiviluoto, Santeri; Oh‐hora, Masatsugu; Luyten, Tomas; Smedt, Humbert De; Parys, Jan B.; Missiaen, Ludwig; Bultynck, Geert

doi:10.1016/j.ceca.2010.08.003

Cited by 15 publications

(19 citation statements)

References 49 publications

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“…Peptides were added 2 min before IP 3 till 2 min after IP 3 . IICR was plotted as fractional loss, representing the amount of Ca 2+ leaving the store in a 2-min time period divided by the total store Ca 2+ content at that time point as a function of time [64]. …”

Section: Methodsmentioning

confidence: 99%

The trans-membrane domain of Bcl-2α, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition

et al. 2016

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The anti-apoptotic Bcl-2 protein is emerging as an efficient inhibitor of IP3R function, contributing to its oncogenic properties. Yet, the underlying molecular mechanisms remain not fully understood. Using mutations or pharmacological inhibition to antagonize Bcl-2's hydrophobic cleft, we excluded this functional domain as responsible for Bcl-2-mediated IP3Rs inhibition. In contrast, the deletion of the C-terminus, containing the trans-membrane domain, which is only present in Bcl-2α, but not in Bcl-2β, led to impaired inhibition of IP3R-mediated Ca2+ release and staurosporine-induced apoptosis. Strikingly, the trans-membrane domain was sufficient for IP3R binding and inhibition. We therefore propose a novel model, in which the Bcl-2's C-terminus serves as a functional anchor, which beyond mere ER-membrane targeting, underlies efficient IP3R inhibition by (i) positioning the BH4 domain in the close proximity of its binding site on IP3R, thus facilitating their interaction; (ii) inhibiting IP3R-channel openings through a direct interaction with the C-terminal region of the channel downstream of the channel-pore. Finally, since the hydrophobic cleft of Bcl-2 was not involved in IP3R suppression, our findings indicate that ABT-199 does not interfere with IP3R regulation by Bcl-2 and its mechanism of action as a cell-death therapeutic in cancer cells likely does not involve Ca2+ signaling.

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Section: Methodsmentioning

confidence: 99%

The trans-membrane domain of Bcl-2α, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition

et al. 2016

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“…Ca 2+ release was plotted as fractional loss (%/2 min) as a function of time as previously described. 46 The fractional loss represents the amount of Ca 2+ leaving the store in a 2-min time period divided by the total store Ca 2+ content at that time point. The effect of these BH4-domain peptides on IICR was tested by preincubating the peptides 4 min before exposing the stores to IP 3 .…”

Section: Methodsmentioning

confidence: 99%

Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl

Monaco¹,

Decrock

Akl³

et al. 2011

Cell Death Differ

168

248

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Antiapoptotic B-cell lymphoma 2 (Bcl-2) targets the inositol 1,4,5-trisphosphate receptor (IP3R) via its BH4 domain, thereby suppressing IP3R Ca2+-flux properties and protecting against Ca2+-dependent apoptosis. Here, we directly compared IP3R inhibition by BH4-Bcl-2 and BH4-Bcl-Xl. In contrast to BH4-Bcl-2, BH4-Bcl-Xl neither bound the modulatory domain of IP3R nor inhibited IP3-induced Ca2+ release (IICR) in permeabilized and intact cells. We identified a critical residue in BH4-Bcl-2 (Lys17) not conserved in BH4-Bcl-Xl (Asp11). Changing Lys17 into Asp in BH4-Bcl-2 completely abolished its IP3R-binding and -inhibitory properties, whereas changing Asp11 into Lys in BH4-Bcl-Xl induced IP3R binding and inhibition. This difference in IP3R regulation between BH4-Bcl-2 and BH4-Bcl-Xl controls their antiapoptotic action. Although both BH4-Bcl-2 and BH4-Bcl-Xl had antiapoptotic activity, BH4-Bcl-2 was more potent than BH4-Bcl-Xl. The effect of BH4-Bcl-2, but not of BH4-Bcl-Xl, depended on its binding to IP3Rs. In agreement with the IP3R-binding properties, the antiapoptotic activity of BH4-Bcl-2 and BH4-Bcl-Xl was modulated by the Lys/Asp substitutions. Changing Lys17 into Asp in full-length Bcl-2 significantly decreased its binding to the IP3R, its ability to inhibit IICR and its protection against apoptotic stimuli. A single amino-acid difference between BH4-Bcl-2 and BH4-Bcl-Xl therefore underlies differential regulation of IP3Rs and Ca2+-driven apoptosis by these functional domains. Mutating this residue affects the function of Bcl-2 in Ca2+ signaling and apoptosis.

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“…This regulation implicated the activation of the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (AKT) signaling pathway and would act upon a protein complex involving polycystin-2/IP 3 R/STIM1. It should be pointed out, however, that in a study comparing STIM1 −/− and wild-type MEF cells, no evidence was found for a direct interaction between STIM1 and the IP 3 R, but the effects on IICR were attributed to changes in the connections between the ER and plasma membrane [97]. …”

Section: Disturbed Cellular Ca2+ Fluxes In Adpkdmentioning

confidence: 99%

Polycystins and cellular Ca2+ signaling

Mekahli

Parys

Bultynck

et al. 2012

Cell. Mol. Life Sci.

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The cystic phenotype in autosomal dominant polycystic kidney disease is characterized by a profound dysfunction of many cellular signaling patterns, ultimately leading to an increase in both cell proliferation and apoptotic cell death. Disturbance of normal cellular Ca2+ signaling seems to be a primary event and is clearly involved in many pathways that may lead to both types of cellular responses. In this review, we summarize the current knowledge about the molecular and functional interactions between polycystins and multiple components of the cellular Ca2+-signaling machinery. In addition, we discuss the relevant downstream responses of the changed Ca2+ signaling that ultimately lead to increased proliferation and increased apoptosis as observed in many cystic cell types.

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STIM1, but not STIM2, is required for proper agonist-induced Ca2+ signaling

Cited by 15 publications

References 49 publications

The trans-membrane domain of Bcl-2α, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition

The trans-membrane domain of Bcl-2α, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition

Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl

Polycystins and cellular Ca2+ signaling

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