- β-Adrenergic receptor-coupled Gs protein function was measured in 26 depressed patients through cholera toxin-sensitive, isoproterenol-induced increases in 3 H-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 α through immunoblot analysis by use of polyclonal antibodies against Gsc α subunit, it was found that Gs α 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 β -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.