Impaired endoplasmic reticulum stress response in B-lymphoblasts from patients with bipolar-I disorder.
BACKGROUND
Aberrant intracellular calcium (Ca2+) signaling in patients with bipolar-I disorder (BD-I) suggests disturbed endoplasmic reticulum (ER) function in BD. We examined whether the ER stress response is altered in BD-I patients and the relationship to basal intracellular Ca2+ levels ([Ca2+]B), in B lymphoblasts (BLCLs) from BD-I patients.


METHODS
Endoplasmic reticulum stress-induced X-box binding protein 1 (XBP1), C/EBP homologous protein (CHOP), and GRP78 expression in BLCLs from BD-I subjects stratified on elevated or normal [Ca2+]B and control subjects were determined by real-time quantitative reverse transcription polymerase chain reaction. The XBP1 -116C/G polymorphism, which impairs the XBP1 loop in the ER stress response, were genotyped with a TaqMan-based assay.


RESULTS
Compared with control subjects, thapsigargin- and tunicamycin-induced increases in XBP1 and CHOP but not GRP78 messenger RNA levels were significantly lower in BD-I patients. However, induction of these genes did not differ significantly in the two BD-I subgroups stratified on [Ca2+]B. Furthermore, the attenuated XBP1 induction cannot be explained solely by differences of XBP1 -116C/G genotype frequency.


CONCLUSIONS
Our findings suggest that the ER stress response is impaired in BD-I patients but irrespective of altered intracellular Ca2+ homeostasis as reflected in elevated [Ca2+]B. Moreover, an effect of XBP1 -116C/G polymorphism could not account for the attenuated XBP1 induction in bipolar-I disorder observed in this study.
So
Jonathan
J
Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
Warsh
Jerry J
JJ
Li
Peter P
PP
D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1
C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D051742:Transcription Factor CHOP; D002118:Calcium