Associated disturbances in calcium homeostasis and G protein–mediated cAMP signaling in bipolar I disorder

Background: Evidence of extensive cross-talk between calcium (Ca2+)- and cAMP-mediated signaling systems suggests that previously reported abnormalities in Ca2+ 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 β-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 ([Ca2+]B). cAMP was measured by radioimmunoassay and [Ca2+]B by ratiometric fluorometry with fura-2. Results: Isoproterenol- (10 μM) stimulated cAMP formation was lower in intact B lymphoblasts from BP-I patients with high [Ca2+]B (≥ 2 SD above the mean concentration of healthy subjects) compared with patients having normal B lymphoblast [Ca2+]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 [Ca2+]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 β-adrenergic receptor sensitivity and G protein–mediated cAMP signaling occur in conjunction with altered Ca2+ homeostasis in those BP-I patients with high B lymphoblast [Ca2+]B.