TRPM2 mediated intracellular Zn2{+} release triggers pancreatic beta cell death

Reactive oxygen species (ROS) can cause pancreatic β-cell death by activating the pro-apoptotic transient receptor potential (melastatin)2 (TRPM2) channels. Cell death was attributed to the ability of these channels to raise cytosolic [Ca2+]. Recent studies, however, revealed that TRPM2 channels can also conduct Zn2+, but the physiological relevance of this property is enigmatic. Given Zn2+ is cytotoxic, we asked if TRPM2 channels can permeate sufficient Zn2+ to affect cell viability. To address this, we used the INS1 β-cell line, HEK-293 cells transfected with TRPM2 and pancreatic islets. H2O2 activation of TRPM2 channels increases the cytosolic levels of both Ca2+ and Zn2+ and causes apoptotic cell death. Interestingly, chelation of Zn2+ alone was sufficient to prevent β-cell death. The source of the cytotoxic Zn2+ is intracellular, found largely sequestered in lysosomes. Lysosomes express TRPM2 channels, providing a potential route for Zn2+ release. Zn2+ release is potentiated by extracellular Ca2+ entry, indicating that Ca2+-induced Zn2+ release leads to apoptosis. Knock-out of TRPM2 channels protects mice from β-cell death and hyperglycaemia induced by multiple low-dose streptozotocin administration. These results argue that TRPM2-mediated, Ca2+ potentiated Zn2+ release underlies ROS-induced β-cell death and Zn2+, rather than ...

Source: BJ Signal - January 6, 2015 Category: Biochemistry Authors: P T Manna, T S Munsey, N Abuarab, F Li, A Asipu, G Howell, A Sedo, W Yang, J Naylor, D J Beech, L Jiang, A Sivaprasadarao Tags: BJ Signal Source Type: research