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 Gs and the inhibitory G-protein Gi 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 (Gs) 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 Gs but not by Gi) and platelets (where AC is regulated by both Gs and Gi) 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 Gi 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 Gs and Gi through coincidence detection, while such coincidence detection by platelet AC may be impaired in patients with depressive disorders