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 AlF 4 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 ΔAlF 4) 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 ΔAlF 4 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 ΔAlF 4 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.