guanylyl-imidodiphosphate and Bipolar-Disorder

beta-Adrenergic receptor-coupled Gs protein function was measured in 26 depressed patients through cholera toxin-sensitive, isoproterenol-induced increases in 3H-Gpp(NH)p binding capacity to mononuclear leukocytes (MNL). Highly significant reductions in receptor-coupled Gs protein function were observed in the depressed patients: 2.0 +/- 1.3% increases in guanine nucleotide-binding capacity, in comparison with the control group values of 28.3 +/- 6.9%. Similar reductions in Gs protein function were detected in both uni- and bipolar depressed patients. A significant negative correlation was found between receptor-coupled Gs protein measures and the severity of depression. Adding semiquantitative measures of MNL Gs alpha through immunoblot analysis by use of polyclonal antibodies against Gs alpha subunit, it was found that Gs alpha relative immunoreactivity was reduced from 100 +/- 2.0% in the control group of subjects to 75.9 +/- 2.3% in the depressed patients. We have previously described hyperfunctional Gs proteins in leukocytes of patients with mania. The present findings of reduced function of Gs in depressed patients suggests receptor-coupled Gs protein activity as a biochemical parameter indicatory of the affective state. Reduced receptor-coupled Gs protein function may reflect reduced levels of the beta-adrenergic receptor previously shown in leukocytes of depressed patients; however, our complementary immunoblot studies suggest a direct, postreceptor, quantitative, and functional reduction in Gs protein in MNL of depressed patients.

Topics: Adult; Aged; Bipolar Disorder; Depressive Disorder; Female; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Personality Inventory; Receptors, Adrenergic, alpha; Second Messenger Systems; Signal Transduction

In a recent study, we found that lithium inhibits the function of guanine nucleotide-binding proteins, implicating G proteins as the common site for both the antimanic and antidepressant therapeutic effects of lithium. These findings may also suggest that an altered G protein function is of pathophysiological importance in bipolar affective disorder. In the present study, the coupling of both muscarinic-cholinergic receptors and beta-adrenergic receptors to pertussis toxin-sensitive G proteins or cholera toxin-sensitive G proteins was compared among untreated manic patients, lithium-treated euthymic bipolar patients, and healthy volunteers using mononuclear leukocyte (MNL) membrane preparations. Hyperactive function of G proteins was detected in untreated manic patients. Both isoproterenol-induced and carbamylcholine-induced increases in Gpp(NH)p binding capacity were twofold to threefold higher than the increases observed in healthy volunteers. On the other hand, lithium-treated euthymic bipolar patients showed G protein responses to agonist activation that were no different from the healthy volunteers. Altered G protein function may be of pathophysiological importance in bipolar affective disorder.

Topics: Adenosine Diphosphate; Adult; Bipolar Disorder; Female; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Humans; Leukocytes, Mononuclear; Lithium; Male; Middle Aged