SIGNAL-TRANSDUCTION BY PLATELET ADENYLATE-CYCLASE - ALTERATIONS IN DEPRESSED-PATIENTS MAY REFLECT IMPAIRMENT IN THE COORDINATED INTEGRATIONOF 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 coin cidence 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 (GTP gamma S) or AlF4 ion postreceptor-stimulat ed 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 (Delta G TP gamma S or Delta AlF4) between postreceptor measures of AC in monon uclear leukocytes (where AC is regulated by G(s) but not by G(i)) and platelets (where AC is regulated by both (s) and G(i)) were highly sig nificant, In controls, the relationships between Delta GTP gamma S or Delta AlF4 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 Delta GTP gamma S or Delta AlF4 and basal, agonist-stimulated, and the fold-stim ulation of agonist-stimulated platelet AC activities were not observed in depressed patients. Conclusions: Our results suggest that in contr ols, platelet AC enzyme activity is determined (in part) by the coordi nated integration of signals from G(s) and G(i) through coincidence de tection, while such coincidence detection by platelet AC may be impair ed in patients with depressive disorders. (C) 1998 Society of Biologic al Psychiatry.