Abstract
Biliary acute pancreatitis (AP) is a serious condition, which currently has no specific treatment. Taurolithocholic acid 3-sulfate (TLC-S) is one of the most potent bile acids causing cytosolic Ca2+ overload in pancreatic acinar cells (PACs), which results in premature activation of digestive enzymes and necrosis, hallmarks of AP. The inositol 1,4,5-trisphosphate receptor (IP3R) and the ryanodine receptor (RyR) play major roles in intracellular Ca2+ signaling. Inhibition of these endoplasmic reticulum-located channels suppresses TLC-S-induced Ca2+ release and necrosis, decreasing the severity of AP. Anti-apoptotic B-cell lymphoma (Bcl)-2-family members, such as Bcl-2 and Bcl-XL, have emerged as important modulators of IP3Rs and RyRs. These proteins contain four Bcl-2 homology (BH) domains of which the N-terminal BH4 domain exerts critical roles in regulating intracellular Ca2+ release channels. The BH4 domain of Bcl-2, but not of Bcl-XL, binds to and inhibits IP3Rs, whereas both BH4 domains inhibit RyRs. Although clear cytoprotective effects have been reported for these BH4 domains, it remains unclear whether they are capable of inhibiting pathological Ca2+-overload, associated with AP. Here we demonstrate in PACs that the BH4 domains of Bcl-2 and Bcl-XL inhibit RyR activity in response to the physiological agonist cholecystokinin. In addition, these BH4 domains inhibit pathophysiological TLC-S-induced Ca2+ overload in PACs via RyR inhibition, which in turn protects these cells from TLC-S-induced necrosis. This study shows for the first time the therapeutic potential of BH4 domain function by inhibiting pathological RyR-mediated Ca2+ release and necrosis, events that trigger AP.
Highlights
The anti-apoptotic B-cell lymphoma 2 (Bcl-2)-family members, like Bcl-2 and Bcl-XL, are critically involved in maintaining mitochondrial integrity by scavenging and inhibiting pro-apoptotic Bcl-2-family members, such as Bax and Bak[1]
By employing primary isolated mouse pancreatic acinar cells (PACs), we show that peptides derived from the BH4 domains of Bcl-2 and Bcl-XL inhibit both physiological and pathophysiological ryanodine receptor (RyR)-mediated Ca2+ release, as well as protect PACs from Taurolithocholic acid 3-sulfate (TLC-S)-induced necrosis
In the first set of experiments, we aimed to assess the ability of the BH4 domains of Bcl-2 and Bcl-XL to inhibit IP3R or RyR-mediated Ca2+ release in isolated PACs
Summary
The anti-apoptotic B-cell lymphoma 2 (Bcl-2)-family members, like Bcl-2 and Bcl-XL, are critically involved in maintaining mitochondrial integrity by scavenging and inhibiting pro-apoptotic Bcl-2-family members, such as Bax and Bak[1]. This interaction occurs via the hydrophobic cleft, formed by the Bcl-2 homology (BH) domain 1, 2, and 3, of anti-apoptotic Bcl-2 proteins and the BH3 domain of the pro-apoptotic family members. The BH4 domain, is critical for the antiapoptotic properties of Bcl-22–4. Besides neutralizing pro-apoptotic Bcl-2-family members, anti-apoptotic Bcl-2 proteins emerged as critical modulators of intracellular Ca2+ signaling[5,6,7]. At the ER, Bcl-2 directly inhibits the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)[3,4], a ubiquitously expressed IP3-gated ER-located Ca2+ release channel[10]
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