Protracted lithium treatment protects against the ER stress elicited by thapsigargin in rat PC12 cells: roles of intracellular calcium, GRP78 and Bcl-2.
We investigated the cytoprotective effects of lithium, the mood-stabilizer, on thapsigargin-induced stress on the endoplasmic reticulum (ER) in rat PC12 cells. Protracted lithium pretreatment of PC12 cells elicited cytoprotection against thapsigargin-induced cytotoxicity. Lithium protection was concurrent with inhibition of thapsigargin-induced intracellular calcium increase and with elevated expression of the molecular chaperone GRP78. Moreover, lithium pretreatment upregulated the antiapoptotic protein Bcl-2, and blocked Bcl-2 downregulation elicited by thapsigargin. Prior to the induction of GRP78, lithium treatment alone increased the expression of c-Fos whose induction by ER stress is necessary for GRP78 induction. Curcumin, an inhibitor of transcription factor AP-1, blocked lithium cytoprotection against thapsigargin cytotoxicity. Thus, the induction of GRP78 and Bcl-2, and activation of AP-1 likely contribute to lithium-induced protection against cytotoxicity resulting from ER stress. Additionally, thapsigargin-induced cytotoxicity was suppressed by pretreatment with another mood-stabilizer, valproate, indicating that cytoprotection against ER stress is a common action of mood-stabilizing drugs.
Hiroi
T
T
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1363, USA.
Wei
H
H
Hough
C
C
Leeds
P
P
Chuang
D-M
DM
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006360:Heat-Shock Proteins / Q000502:physiology*; D008094:Lithium / Q000494:pharmacology*; D018832:Molecular Chaperones / Q000502:physiology*; D018696:Neuroprotective Agents; D016716:PC12 Cells; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019284:Thapsigargin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP
D002118:Calcium; D000252:Calcium-Transporting ATPases; D003474:Curcumin; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D008094:Lithium; D018832:Molecular Chaperones; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D019284:Thapsigargin; D018808:Transcription Factor AP-1; D014635:Valproic Acid; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP