Bcl-2 Protein Family Members: Versatile Regulators of Calcium Signaling in Cell Survival and Apoptosis

Abstract

Bcl-2 family members are important regulators of cell survival and cell death. Researchers have focused mainly on mitochondria, where both proapoptotic and antiapoptotic family members function to regulate the release of cytochrome c and other mediators of apoptosis. However, as reviewed here, Bcl-2 family members also operate on another front, the endoplasmic reticulum (ER), to both positively and negatively regulate the release of Ca2+. There is abundant evidence that Ca2+ signals trigger apoptosis in response to a wide variety of agents and conditions. Conversely, Ca2+ signals can also mediate cell survival. Recent findings indicate that Bcl-2 interacts with inositol 1,4,5-trisphosphate (IP3) receptor Ca2+ channels on the ER, regulating their opening in response to IP3- and thus inhibiting IP3-mediated Ca2+ signals that induce apoptosis while enhancing Ca2+ signals that support cell survival.

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

“…4). 29 If such a mechanism operates in neurons, a reduction in the release of Ca 2+ from the internal store and the subsequent decline in the level of Ca 2+ would support the notion that the upregulation of Ca 2+ signaling is responsible for driving memory loss in AD.…”

“…It would seem that changes in the cyclic AMP signaling pathway can either enhance or reduce the tonic excitatory drive and this would have repercussions on the generation of the gamma the ability of Ins(1,4,5)P 3 to open the Ins(1,4,5)P 3 R channel to release Ca 2+ from the ER. 29 The low level of Bcl-2 will enhance apoptosis and will also reduce its inhibitory effect on Ins(1,4,5) P 3 -induced Ca 2+ release that may explain the increase in both resting and activated levels of Ca 2+ that are a characteristic feature of BD. 30 Inositol depletion hypothesis of bipolar disorder.…”

The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family

“…Given that calcineurin is activated by Ca 2 þ , ER Ca 2 þ release may contribute to cristae remodeling through both mitochondrial Ca 2 þ transmission and DRP1 phosphorylation. However, as calcineurin activity is not restricted to proapoptotic conditions (Groenendyk et al, 2004;Rong and Distelhorst, 2008), DRP1 activation during apoptosis likely involves additional regulatory factors. Potential candidates for apoptosis-specific DRP1 activation include BAX and/or BAK.…”

“…These possibilities, however, are not mutually exclusive, and, in any case, would all have a protective effect with respect to apoptosis. The role of BCL-2/BCL-xL in ER Ca 2 þ signaling has recently been reviewed elsewhere (Distelhorst and Shore, 2004;Pinton and Rizzuto, 2006;Rong and Distelhorst, 2008).…”

“…For example, ERrestricted BCL-2 and BCL-xL can inhibit apoptosis initiated by diverse stimuli (Hacki et al, 2000;Germain et al, 2005;Mathai et al, 2005;Bhatt et al, 2008) and BAX/BAK (Nutt et al, 2002b;Zong et al, 2003;Chami et al, 2004), as well as a number of BH3-only proteins (Elyaman et al, 2002;Gao et al, 2005;Luo et al, 2005;Armstrong et al, 2007;Hetz et al, 2007;Puthalakath et al, 2007;Szegezdi et al, 2008;Upton et al, 2008) can promote apoptosis through their activity at the ER. BCL-2 family proteins at the ER regulate apoptosis through both direct modulation of signaling pathways leading to caspase activation and through the modulation of ER Ca 2 þ signaling (Oakes et al, 2006;Rong and Distelhorst, 2008). Conversely, BCL-2 family proteins themselves can be modulated by signals emanating from the ER, and therefore have an essential role in apoptotic pathways initiated by ER stress (Oakes et al, 2006;Hetz, 2007).…”