In this study, CJ caused ER Ca2+ depletion through IP3R, resulting in store-operated Ca2+ entry through CRAC channels [66]. sword for both life as well as death, and current experimental evidence supports a model in which Ca2+ homeostasis and SERCA activity represent a nodal point that controls cell survival. Pharmacological or genetic targeting of this axis constitutes an incredible therapeutic potential to treat different diseases sharing similar biological disorders. the present review focuses on the specific role of the Sarco/Endoplasmic Reticulum Ca2+ ATPase (SERCA) in cell death and survival (Figures 1 and ?and22). Open in a separate window Physique 1 Basic processes of cell deathCell death occurs through three different means: apoptosis, autophagy and necrosis Open in a separate window Physique 2 Overview of intracellular Ca2+ signaling and its implications in cell death and survivalMajor organelles and players regulating Ca2+ influx and efflux during the process of cell death. and Bcl-2, B-cell lymphoma 2; GRP75, glucose-regulated protein 75; IP3R, inositol1,4,5-trisphosphate (IP3) receptor; LTCC, L-type Ca2+ channel; MCU, mitochondrial Ca2+ uniporter; mPTP, mitochondrial permeabilization transition pore; NCX, Na+/Ca2+ exchanger; NFAT, nuclear factor of activated T lymphocytes; PMCA, plasma-membrane Ca2+ ATPase; RyR, Ryanodine Receptor; SERCA, Sarco/Endoplasmic Reticulum Ca2+ ATPase; STIM1, Stromal conversation molecule 1; TPC2, two-pore channel 2; TRPC, transient receptor potential canonical; VDAC, voltage-dependent anion channel. See text for further explanations 1.2. Endoplasmic Reticulum (ER) stress: role of the B-cell lymphoma 2 (Bcl-2) Ca2+ rheostat in cell death and survival The ER plays a critical role in Ca2+ handling, protein synthesis and protein processing [2C5]. Impairment of these functions occurs in various pathological conditions resulting in the accumulation of misfolded proteins in the ER, which initiates the ER stress response [6C8]. ER stress triggers the unfolded protein response (UPR) and protein degradation pathways, such as autophagy and apoptosis. The UPR is initiated in response to unfolded proteins and is initially adaptive and pro-survival, but progresses to apoptosis when ER stress becomes chronic, irreversible, and when the UPR is usually ineffective [6C9]. The B-cell lymphoma 2 (Bcl-2) protein family is usually a central a part of protein complexes that modulate the response to ER stress, with apoptosis and autophagy as the possible end-results [2, 10C12]. Bcl-2 is usually thus described as a rheostat [2] belonging to a large family of proteins comprising pro-apoptotic and anti-apoptotic molecules [2, 12]. The pro-apoptotic members of the Bcl-2 family trigger mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c and to the assembly of the apoptosome [13C15]. The pro-apoptotic members of Bcl-2, PUMA and NOXA, are BH-3 only proteins participating in ER stress-induced apoptosis in a p53-dependent manner [16]. The CCAAT-enhancer-binding protein homologous protein (CHOP) is usually induced by ER stress and mediates apoptosis [6]. PUMA was shown to be induced by CHOP, while NOXA is an additional apoptosis mediator induced by the Activation of Transcription 4 (ATF4) [2, 17, (R)-3-Hydroxyisobutyric acid 18]. CHOP induces apoptosis by a variety of mechanisms [6]. In particular, CHOP induces the expression of ER oxidoreductin 1 (ERO1), which activates the ER Ca2+ release channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) [6]. CHOP also upregulates the pro-apoptotic protein BIM and down-regulates the pro-survival protein Bcl-2 [18]. More complex roles are played by Bcl-2 family members, such as Sirt6 IRE1 (Inositol-Requiring transmembrane kinase/Endonuclease ) which is usually stabilized by Bax/Bak, two pro-apoptotic members of the Bcl-2 family [2, 19]. In this regard, it has been shown that in apoptosis, Bax and Bak translocate to the ER membrane and promote Ca2+ release from the ER lumen [15, 20], either by allowing Ca2+ exit through the Bax/Bak oligomerization-formed ionic pores [21] or indirectly by favoring IP3R opening [13]. In turn, Ca2+ leakage from ER recruits more Bax molecules from the cytosol to ER membranes [20], further amplifying the apoptotic signal [22]. Furthermore, earlier studies have addressed the more complex role of Bax and Bak in apoptosis related to ER-mitochondria Ca2+ signaling [23]. Bak and Bax double knockout cells had reduced ER Ca2+ stores available for ER Ca2+ release and mitochondrial Ca2+ uptake, making the cells less prone to apoptosis induced by ER Ca2+ release; the latter phenotype was reversed by SERCA expression [23]. In the same study, Bax targeting to mitochondria selectively restored apoptosis to “BH3-only” signals [23]. The fine balance between pro- and.Furthermore, changes in ER membrane fluidity caused by increased obesity-induced phospholipids incorporation into the ER membrane results in dysfunctional SERCA2b and amplification of ER Ca2+ imbalance [123, 130]. 14 different SERCA isoforms encoded by three genes whose expressions are species- and tissue-specific. Altered SERCA expression and activity results in cellular malignancy and induction of ER stress and ER stress-associated apoptosis. The role of SERCA misregulation in the control of apoptosis in various cell types and disease setting with prospective therapeutic implications is the focus of this review. Ca2+ is usually a double edge sword for both life as well as death, and current experimental evidence supports a model in which Ca2+ homeostasis and SERCA activity represent a nodal point that controls cell survival. Pharmacological or genetic targeting of this axis constitutes an incredible therapeutic potential to treat different diseases sharing similar biological disorders. the present review focuses on the specific role of the Sarco/Endoplasmic Reticulum Ca2+ ATPase (SERCA) (R)-3-Hydroxyisobutyric acid in cell death and survival (Figures 1 and ?and22). Open in a separate window Figure 1 Basic processes of cell deathCell death occurs through three different means: apoptosis, autophagy and necrosis Open in a separate window Figure 2 Overview of intracellular Ca2+ signaling and its implications in cell death and survivalMajor organelles and players regulating Ca2+ influx and efflux during the process of cell death. and Bcl-2, B-cell lymphoma 2; GRP75, glucose-regulated protein 75; IP3R, inositol1,4,5-trisphosphate (IP3) receptor; LTCC, L-type Ca2+ channel; MCU, mitochondrial Ca2+ uniporter; mPTP, mitochondrial permeabilization transition pore; NCX, Na+/Ca2+ exchanger; NFAT, nuclear factor of activated T lymphocytes; PMCA, plasma-membrane Ca2+ ATPase; RyR, Ryanodine Receptor; SERCA, Sarco/Endoplasmic Reticulum Ca2+ ATPase; STIM1, Stromal interaction molecule 1; TPC2, two-pore channel 2; TRPC, transient receptor potential canonical; VDAC, voltage-dependent anion channel. See text for further explanations 1.2. Endoplasmic Reticulum (ER) stress: role of the B-cell lymphoma 2 (Bcl-2) Ca2+ rheostat in cell death and survival The ER plays a critical role in Ca2+ handling, protein synthesis and protein processing [2C5]. Impairment of these functions occurs in various pathological conditions resulting in the accumulation of misfolded proteins in the ER, which initiates the ER stress response [6C8]. ER stress triggers the unfolded protein response (UPR) and protein degradation pathways, such as autophagy and apoptosis. The UPR is initiated in response to unfolded proteins and is initially adaptive and pro-survival, but (R)-3-Hydroxyisobutyric acid progresses to apoptosis when ER stress becomes chronic, irreversible, and when the UPR is ineffective [6C9]. The B-cell lymphoma 2 (Bcl-2) protein family is a central part of protein complexes that modulate the response to ER stress, with apoptosis and autophagy as the possible end-results [2, 10C12]. Bcl-2 is thus described as a rheostat [2] belonging to a large family of proteins comprising pro-apoptotic and anti-apoptotic molecules [2, 12]. The pro-apoptotic members of the Bcl-2 family trigger mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c and to the assembly of the apoptosome [13C15]. The pro-apoptotic members of Bcl-2, PUMA and NOXA, are BH-3 only proteins participating in ER stress-induced apoptosis in a p53-dependent manner [16]. The CCAAT-enhancer-binding protein homologous protein (CHOP) is induced by ER stress and mediates apoptosis [6]. PUMA was shown to be induced by CHOP, while NOXA is an additional apoptosis mediator induced by the Activation of Transcription 4 (ATF4) [2, 17, 18]. CHOP induces apoptosis by a variety of mechanisms [6]. In particular, CHOP induces the expression of ER oxidoreductin 1 (ERO1), which activates the ER Ca2+ release channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) [6]. CHOP also upregulates the pro-apoptotic protein BIM and down-regulates the pro-survival protein Bcl-2 [18]. More complex roles are played by Bcl-2 family members, such as IRE1 (Inositol-Requiring transmembrane kinase/Endonuclease ) which is stabilized by Bax/Bak, two pro-apoptotic members of the Bcl-2 family [2, 19]. In this regard, it has been shown that in apoptosis, Bax and Bak translocate to the ER membrane and promote Ca2+ release from the ER lumen [15, 20], either by allowing Ca2+ exit through the Bax/Bak oligomerization-formed ionic pores [21] or indirectly by favoring IP3R opening [13]. In turn, Ca2+ leakage from ER recruits more Bax molecules from the cytosol to ER membranes [20], further amplifying the apoptotic signal [22]. Furthermore, earlier.