Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival

Chang, Ming Jin; Zhong, Fei; Lavik, Andrew R.; Parys, Jan B.; Berridge, Michael J.; Distelhorst, Clark W.

doi:10.1073/pnas.1323098111

Cited by 47 publications

(52 citation statements)

References 37 publications

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“…In addition to pro-apoptotic Bcl2 family members such as Bax, BH4 domains can also interact with inositol 1,4,5-trisphosphate receptors (IP 3 Rs) such as IP 3 R1 (Chang et al, 2014; Distelhorst and Bootman, 2011; Greenberg et al, 2014; Oakes et al, 2005; Rong et al, 2009). Notably, IP 3 R1 has been implicated in injury-induced axon degeneration (Villegas et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration

Pease-Raissi

Pazyra-Murphy

et al. 2017

Neuron

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Summary Chemotherapy induced peripheral neuropathy (CIPN) is a debilitating side effect of many cancer treatments. The hallmark of CIPN is degeneration of long axons required for transmission of sensory information; axonal degeneration causes impaired tactile sensation and persistent pain. Currently the molecular mechanisms of CIPN are not understood, and there are no available treatments. Here we show that the chemotherapeutic agent paclitaxel triggers CIPN by altering IP3 receptor phosphorylation and intracellular calcium flux, and activating calcium-dependent calpain proteases. Concomitantly paclitaxel impairs axonal trafficking of RNA-granules and reduces synthesis of Bclw (bcl2l2), a Bcl2 family member that binds IP3R1 and restrains axon degeneration. Surprisingly, Bclw or a stapled peptide corresponding to the Bclw BH4 domain interact with axonal IP3R1 and prevent paclitaxel-induced degeneration, while Bcl2 and BclxL cannot do so. Together these data identify a Bclw-IP3R1-dependent cascade that causes axon degeneration, and suggest Bclw-mimetics could provide effective therapy to prevent CIPN.

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Section: Resultsmentioning

confidence: 99%

Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration

Pease-Raissi

Pazyra-Murphy

et al. 2017

Neuron

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“…However, it is unclear if Bcl-2 inhibits Ca 2+ signaling directly by binding to the channel or if it acts indirectly, as a hub in a protein complex that influences channel phosphorylation (38). Conversely, we demonstrated that Bcl-x L , Bcl-2, and Mcl-1 bind to the carboxyl (C)-terminus of all three InsP 3 R isoforms, and showed that these interactions activated single InsP 3 R channels and promoted InsP 3 R-mediated Ca 2+ release and apoptosis resistance (27,31,32).…”

Section: Significancementioning

confidence: 99%

Biphasic regulation of InsP ₃ receptor gating by dual Ca ²⁺ release channel BH3-like domains mediates Bcl-x _L control of cell viability

Yang

Vais

et al. 2016

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

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Antiapoptotic Bcl-2 family members interact with inositol trisphosphate receptor (InsP 3 R) Ca 2+ release channels in the endoplasmic reticulum to modulate Ca 2+ signals that affect cell viability. However, the molecular details and consequences of their interactions are unclear. Here, we found that Bcl-x L activates single InsP 3 R channels with a biphasic concentration dependence. The Bcl-x L Bcl-2 homology 3 (BH3) domain-binding pocket mediates both high-affinity channel activation and low-affinity inhibition. Bcl-x L activates channel gating by binding to two BH3 domain-like helices in the channel carboxyl terminus, whereas inhibition requires binding to one of them and to a previously identified Bcl-2 interaction site in the channelcoupling domain. Disruption of these interactions diminishes cell viability and sensitizes cells to apoptotic stimuli. Our results identify BH3-like domains in an ion channel and they provide a unifying model of the effects of antiapoptotic Bcl-2 proteins on the InsP 3 R that play critical roles in Ca 2+ signaling and cell viability.T he inositol trisphosphate receptors (InsP 3 R) are a family of intracellular cation channels that release Ca 2+ from the endoplasmic reticulum (ER) in response to a variety of extracellular stimuli (1). Three InsP 3 R isoforms are ubiquitously expressed and regulate diverse cell processes, including cell viability (1). Activation of the channels by InsP 3 elicits changes in cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ) that provide versatile signals to regulate molecular processes with high spatial and temporal fidelity (1). Regions of close proximity to mitochondria enable localized Ca 2+ release events to be transduced to mitochondria (2, 3). Ca 2+ released from the ER during cell stimulation modulates activities of effector molecules and is taken up by mitochondria to stimulate oxidative phosphorylation and enhance ATP production (4-6) to match energetic supply with enhanced demand. In addition, cells in vivo are constantly exposed to low levels of circulating hormones, transmitters, and growth factors that bind to plasma membrane receptors to provide a background level of cytoplasmic InsP 3 (7) that generates low-level stochastic InsP 3 R-mediated localized or propagating [Ca 2+ ] i signals (8-10). Such signals also play an important role in maintenance of cellular bioenergetics (8). Nevertheless, under conditions of cell stress the close proximity of mitochondria to Ca 2+ release sites may result in mitochondrial Ca 2+ overload and initiate Ca 2+ -dependent forms of cell death, including necrosis and apoptosis (11-13). It has been suggested that high levels of ER Ca 2+ (14-16) and enhanced activity of the InsP 3 R (17-19) promote cell death by providing a higher quantity of released Ca 2+ to mitochondria (3,20,21).Protein interactions modulate the magnitude and quality of InsP 3 R-mediated [Ca 2+ ] i signals that regulate apoptosis and cell viability. Notable in this regard is the Bcl-2 protein family. Proapoptotic Bcl-2-related proteins Bax ...

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“…[12]. In T-lymphocytes however Bcl-2 can dock both DARPP-32 and calcineurin to the IP3R, whereby the PKA-mediated phosphorylation of the latter is antagonized, leading to decreased IP3R-mediated Ca 2+ release [13]. Very recently, in an siRNA screen for the identification of ER Ca 2+ -leak channels, IP3R1 channels emerged as one of the most prominent Ca 2+ -transport systems implicated in ER Ca 2+ leak [14].…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum Ca2+ content decrease by PKA-dependent hyperphosphorylation of type 1 IP3 receptor contributes to prostate cancer cell resistance to androgen deprivation

Boutin¹,

Tajeddine²,

Monaco³

et al. 2015

Cell Calcium

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Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival

Cited by 47 publications

References 37 publications

Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration

Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration

Biphasic regulation of InsP ₃ receptor gating by dual Ca ²⁺ release channel BH3-like domains mediates Bcl-x _L control of cell viability

Endoplasmic reticulum Ca2+ content decrease by PKA-dependent hyperphosphorylation of type 1 IP3 receptor contributes to prostate cancer cell resistance to androgen deprivation

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Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival

Cited by 47 publications

References 37 publications

Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration

Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration

Biphasic regulation of InsP 3 receptor gating by dual Ca 2+ release channel BH3-like domains mediates Bcl-x L control of cell viability

Endoplasmic reticulum Ca2+ content decrease by PKA-dependent hyperphosphorylation of type 1 IP3 receptor contributes to prostate cancer cell resistance to androgen deprivation

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Biphasic regulation of InsP ₃ receptor gating by dual Ca ²⁺ release channel BH3-like domains mediates Bcl-x _L control of cell viability