Effect of ionic stress on apoptosis and the expression of TRPM2 in human olfactory neuroepithelial-derived progenitors

Abstract

Objectives. Disturbed ion homeostasis and apoptosis have been implicated in the pathophysiology of bipolar disorder (BD). TRPM2, a nonselective cation channel, is involved in apoptosis and is possibly linked with BD. In this study, monensin, a sodium ionophore, was used to model the increase [Na⁺]_in and [Ca²⁺]_in seen in BD patients. Methods. Human olfactory neuroepithelial-derived progenitors (ONP), which possess neuronal markers, were utilized to investigate the effects of monensin on apoptosis and the response of TRPM2, and the effects of lithium on the cellular response to monensin. Monensin treatment for 6 h activated caspase-3, -7 and poly(ADP-ribose) polymerase (PARP), inducing apoptosis. Results. [Na⁺]_in increased to twice the basal level and reached steady state after 2 h of 10⁻⁶ M monensin treatment, while [Ca²⁺]_in rose after 6 h of the treatment. Monensin treatment for 24 h decreased expression of the long form of TRPM2, and increased expression of the short form. Lithium (1 mM) pretreatment reduced the [Na⁺]_in and [Ca²⁺]_in elevation caused by monensin, down-regulated the leveles of caspase-3, -7 and PARP, and reduced expression of TRPM2. Conclusions. Our findings suggest that the elevation of [Na⁺]_in and [Ca²⁺]_in induced ONP apoptosis and altered the expression of TRPM2. Lithium pretreatment attenuated the apoptosis induced by ionic stress.

Key words::

• Bipolar disorder
• cellular model
• sodium
• lithium
• calcium

Acknowledgements

Supported by the Dishman Family Foundation (to FR) and NARSAD (to RSE).

Statement of interest

Drs Lu and Roisen have a financial interest in Rhinocyte™ Inc. However, mechanisms have been put into place that prevent them from directly benefiting from this work. None of the other authors have any other conflicts of interest.