Associated disturbances in calcium homeostasis and G protein-mediated cAMP signaling in bipolar I disorder.
BACKGROUND
Evidence of extensive cross-talk between calcium (Ca(2+))- and cAMP-mediated signaling systems suggests that previously reported abnormalities in Ca(2+) homeostasis in bipolar I (BP-I) patients may be linked to disturbances in the function of G proteins that mediate cAMP signaling.


METHODS
To test this hypothesis, the beta-adrenergic agonist, isoproterenol, and the G protein activator, sodium fluoride (NaF), were used to stimulate cAMP production in B lymphoblasts from healthy and BP-I subjects phenotyped on basal intracellular calcium concentration ([Ca(2+)](B)). cAMP was measured by radioimmunoassay and [Ca(2+)](B) by ratiometric fluorometry with fura-2.


RESULTS
Isoproterenol- (10 microM) stimulated cAMP formation was lower in intact B lymphoblasts from BP-I patients with high [Ca(2+)](B) (>/= 2 SD above the mean concentration of healthy subjects) compared with patients having normal B lymphoblast [Ca(2+)](B) and with healthy subjects. Although basal and NaF-stimulated cAMP production was greater in B lymphoblast membranes from male BP-I patients with high versus normal [Ca(2+)](B), there were no differences in the percent stimulation. This suggests the differences in NaF response resulted from higher basal adenylyl cyclase activity.


CONCLUSIONS
These findings suggest that trait-dependent disturbances in processes regulating beta-adrenergic receptor sensitivity and G protein-mediated cAMP signaling occur in conjunction with altered Ca(2+) homeostasis in those BP-I patients with high B lymphoblast [Ca(2+)](B).
Emamghoreishi
M
M
Section of Biochemical Psychiatry, Centre for Addiction and Mental Health, Clarke Site, Toronto, Ontario, Canada.
Li
P P
PP
Schlichter
L
L
Parikh
S V
SV
Cooke
R
R
Warsh
J J
JJ
D000328:Adult; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D001714:Bipolar Disorder / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology*; D002461:Cell Line, Transformed; D000242:Cyclic AMP / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012969:Sodium Fluoride / Q000494:pharmacology
D012969:Sodium Fluoride; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D007545:Isoproterenol; D002118:Calcium