Hyperactive intracellular calcium dynamics in B lymphoblasts from patients with bipolar I disorder.
Substantial evidence implicates abnormalities of intracellular calcium (Ca2+) dynamics in the pathophysiology of bipolar disorder (BD). However, the precise mechanisms underlying such disturbances are poorly understood. To further elaborate the nature of altered intracellular Ca2+ signalling dynamics that occur in BD, we examined receptor- and store-operated Ca2+ responses in B lymphoblast cell lines (BLCLs), which have been found in earlier studies to 'report' BD-associated disturbances. Basal Ca2+ concentrations ([Ca2+]B), and lysophosphatidic acid (LPA)- and thapsigargin-stimulated Ca2+ responses were determined in BLCLs from 52 BD-I patients and 30 healthy comparison subjects using fura-2, and ratiometric fluorometry. ANOVA revealed a significant effect of diagnosis, but not gender, on [Ca2+]B (F1,63=4.4, p=0.04) and the rate of rise (F1,63=5.2, p=0.03) of LPA-stimulated Ca2+ responses in BLCLs from patients compared with those from healthy subjects. A significant genderxdiagnosis interaction on the LPA-induced rate of rise (F1,63=4.6, p=0.03) was accounted for by a faster rate of rise (97%) in BLCLs from BD-I males compared with healthy males but not in those from female patients compared with healthy females. A genderxdiagnosis interaction in thapsigargin-evoked Ca2+ influx (F1,61=3.8, p=0.05) resulted from a significantly higher peak [Ca2+]influx (24%) in BLCLs from female compared with male patients. The results suggest more rapid LPA-stimulated Ca2+ responses occur in BLCLs from BD-I patients compared with controls, which are probably mediated, in part, by canonical transient receptor potential type 3 (TRPC3)-like channels. Additionally, this study highlights sex-dependent differences that can occur in the pathophysiological disturbances involved in BD.
Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Tatiana
T
Perova
Michael J
MJ
Wasserman
Peter P
PP
Li
Jerry J
JJ
Warsh
D000328:Adult; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D001714:Bipolar Disorder / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D004075:Diglycerides / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012737:Sex Factors; D050052:TRPC Cation Channels / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
D004075:Diglycerides; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C032881:lysophosphatidic acid; D002118:Calcium