Effect of ionic stress on apoptosis and the expression of TRPM2 in human olfactory neuroepithelial-derived progenitors.
OBJECTIVE
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 [Ca(2+)](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 [Ca(2+)](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 [Ca(2+)](in) elevation caused by monensin, down-regulated the levels of caspase-3, -7 and PARP, and reduced expression of TRPM2.


CONCLUSIONS
Our findings suggest that the elevation of [Na(+)](in) and [Ca(2+)](in) induced ONP apoptosis and altered the expression of TRPM2. Lithium pretreatment attenuated the apoptosis induced by ionic stress.
Gao
Yonglin
Y
Department of Psychiatry and Behavioral Sciences, University of Louisville, School of Medicine, Louisville, KY 40292, USA.
Lei
Zhenmin
Z
Lu
Chengliang
C
Roisen
Fred J
FJ
El-Mallakh
Rif S
RS
D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D016651:Lithium Carbonate / Q000494:pharmacology; D008297:Male; D008985:Monensin / Q000494:pharmacology; D046569:Neuroepithelial Cells / Q000187:drug effects / Q000378:metabolism; D009831:Olfactory Mucosa / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics*
D004791:Enzyme Inhibitors; D007476:Ionophores; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D016651:Lithium Carbonate; D008985:Monensin; D012964:Sodium; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053179:Caspase 7; D002118:Calcium