Signal transduction by platelet adenylate cyclase: Alterations in depressed patients may reflect impairment in the coordinated integration of cellular signals (coincidence detection)

Background: Adenylate cyclase (AC) responds to distinct but coincident signals from the agonist-stimulated G-protein G(s) and the inhibitory G- protein G(i) by generating a greater output signal-to-noise ratio-i.e., agonist-stimulated to basal ratio (fold-stimulation)-through coincidence detection than that generated by a single input (G(s)) alone. Such coincidence detection by murine brain AC was found to be enhanced during chronic antidepressant treatment with imipramine. Methods: We examined and compared the basal, agonist-stimulated, and guanosine 5'-3-O- (thio)triphosphate (GTPγS) or AlF₄ ion postreceptor-stimulated AC activities in mononuclear leukocytes and platelets from the same blood specimens obtained from depressed patients (n = 27) and control subjects (n = 19). Results: In all subjects, the differences (ΔGTPγS or ΔAlF₄) between postreceptor measures of AC in mononuclear leukocytes (where AC is regulated by G(s) but not by G(i)) and platelets (where AC is regulated by both G(s) and G(i)) were highly significant. In controls, the relationships between ΔGTPγS or ΔAlF₄ and basal, agonist-stimulated, and the fold-stimulation of agonist-stimulated platelet AC resembled the regulation of AC by G(i) in model membrane systems. Comparable relationships between ΔGTPγS or ΔAlF₄ and basal, agonist-stimulated, and the fold-stimulation of agonist-stimulated platelet AC activities were not observed in depressed patients. Conclusions: Our results suggest that in controls, platelet AC enzyme activity is determined (in part) by the coordinated integration of signals from G(s) and G(i) through coincidence detection, while such coincidence detection by platelet AC may be impaired in patients with depressive disorders.