Associated disturbances in calcium homeostasis and G protein-mediated cAMPsignaling in bipolar I disorder

Background: Evidence of extensive cross-talk between calcium (Ca2+)- and cA MP-mediated signaling systems suggests that previously reported abnormaliti es in Ca2+ homeostasis in bipolar I (BP-I) patients may be linked to distur bances in the function of G proteins that mediate cAMP signaling. Methods: To test this hypothesis, the beta -adrenergic agonist, isoproteren ol, and the G protein activator; sodium fluoride (NaF), were used to stimul ate cAMP production in B lymphoblasts from healthy and BP-I subjects phenot yped on basal intracellular calcium concentration ([Ca2+](B)). cAMP was mea sured by radioimmunoassay and [Ca2+](B) by ratiometric fluorometry with fur a-2. Results: Isoproterenol- (10 muM) stimulated cAMP formation was lower in int act B lymphoblasts from BP-I patients with high [Ca2+](B) (greater than or equal to 2 SD above the mean concentration of healthy subjects) compared wi th patients having normal B lymphoblast [Ca2+](B) and with healthy subjects , Although basal and NaF-stimulated cAMP production was greater in B lympho blast membranes from male BP-I patients with high versus normal [Ca2+](B), there were no differences in the percent stimulation This suggests the diff erences in NaF response resulted from higher basal adenylyl cyclase activit y. Conclusions: These findings suggest that trait-dependent disturbances in pr ocesses regulating beta -adrenergic receptor sensitivity and G protein-medi ated cAMP signaling occur in conjunction with altered Ca2+ homeostasis in t hose BP-I patients with high B lymphoblast [Ca2+](B). (C) 2000 Society of B iological Psychiatry.