guanylyl-imidodiphosphate and Depressive-Disorder

Heterotrimeric G proteins were previously implicated in the biochemical mechanisms underlying the pathophysiology and treatment of mood disorders. Low function and immunoreactivity of G proteins were observed in patients with major depression. In the present study the authors evaluated the effects of ECT on the low measures of G proteins in patients with major depression.. Repeated G protein measurements in mononuclear leukocytes of 10 patients with major depression were made. Each patient was examined while untreated and after successive sessions of ECT; 14 normal subjects were also studied. G protein function was evaluated through beta-adrenergic- and muscarinic-agonist-enhanced guanine nucleotide binding capacity, substantiated by quantitative measures of G proteins through immunoblot analyses using polyclonal antibodies against Gs alpha, Gi alpha, and G beta proteins.. Mononuclear leukocytes of patients with depression showed immunoreactive levels of Gs alpha and Gi alpha that were significantly lower than those of normal subjects; the depressed patients also had markedly hypofunctional Gs and Gi. The low levels of G protein function and immunoreactivity were alleviated by ECT. Repeated measurements in the same patients after successive ECT sessions showed that the normalization of G protein measures preceded, and thus predicted, clinical improvement. The function and quantity of Gs and Gi proteins in patients given ECT were significantly correlated.. These findings support the implication of G proteins in the pathophysiology and treatment of mood disorders. G protein measurements in patients with depression may potentially serve not only as a biochemical marker for affective state but also for biochemical prediction and evaluation of responses to ECT.

Topics: Biomarkers; Carbachol; Depressive Disorder; Electroconvulsive Therapy; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Humans; Immunoblotting; Isoproterenol; Leukocytes, Mononuclear

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

G protein function in human mononuclear leucocytes was measured through isoproterenol, carbamylcholine and dopamine-enhanced 3H-Gpp(NH)p binding. Dopamine and carbamylcholine exerted their effects through D5 and M2 receptors, respectively. ADP-ribosylation by bacterial toxins indicates that dopamine and isoproterenol affected Gs, while carbamylcholine affected Gi. Quantitative G proteins measures were conducted through immunoblot analyses with specific polyclonal antibodies against G alpha s, and G alpha i subunits. Simultaneous functional and quantitative measures of G proteins showed significant correlations between function and immunoreactivities. Agonist-enhanced guanine nucleotide exchange is thus suggested as a method for measurement of early events in signal transduction beyond receptors in leucocytes, which can potentially serve for detecting alterations in G proteins measures in human disease.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Adult; Aged; Carbachol; Depressive Disorder; Dopamine; Female; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Humans; Immunoblotting; Isoproterenol; Leukocytes, Mononuclear; Male; Middle Aged; Muscarinic Agonists; Pertussis Toxin; Poly(ADP-ribose) Polymerases; Receptors, Adrenergic, beta; Receptors, Dopamine; Receptors, Muscarinic; Signal Transduction; Virulence Factors, Bordetella

The densities of dopamine-D4 receptors were determined in postmortem samples of caudate nucleus from patients with schizophrenia (n = 9) and age-matched controls (n = 10). D4 receptor binding was defined as the difference between binding sites labeled by [3H]YM-09151-2 (D2 + D3 + D4 receptors) and those by [3H]raclopride, in the presence of 5'-guanylylimidodiphosphate (Gpp(NH)p) (D2 + D3 receptors). D4 receptor binding was measurable in all the subjects with schizophrenia (mean = 3.8 pmol/g tissue) but only in 3/10 controls. To determine the specificity of these findings for schizophrenia, D4 receptor binding was also measured in the caudate nucleus of suicide victims with major depression (n = 6) and age-matched controls (n = 6). A small amount of D4 binding was noted in some of the controls + depressed subjects and there was no significant difference between controls and patients with major depression. The addition of 200 microM Gpp(NH)p to the assay significantly increased the amount of specific binding of [3H]raclopride in control tissues, but not in tissues from subjects with schizophrenia, suggesting an abnormality in the G-protein component coupled to the D2 receptor. [3H]Raclopride binding was also significantly increased by Gpp(NH)p in subjects with major depression. These results confirm a previous report of Seeman et al. (1993) and suggest that measurable D4 receptor binding in the caudate nucleus is more frequent in patients with schizophrenia as compared with normal controls and subjects with major depression and that guanine nucleotides do not enhance [3H]raclopride binding in schizophrenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Benzamides; Caudate Nucleus; Depressive Disorder; Dopamine Antagonists; Female; GTP-Binding Proteins; Guanine Nucleotides; Guanylyl Imidodiphosphate; Humans; In Vitro Techniques; Kinetics; Male; Middle Aged; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; Salicylamides; Schizophrenia