Enhanced transmembrane signaling of 5-ht receptor in platelets of bipolar affective disorder subjects

Recent investigations have suggested that the phosphoinositide (PI) signal transduction system may be involved in the pathophysiology of bipolar affective disorders. Recent studies in our laboratory have implicated altered receptor/G protein coupling and PKC-mediated phosphorylation in bipolar affective disorder and in the clinical action of lithium. The coupling of serotonin receptors to their associated G proteins was examined in frontal cortex of postmortem bipolar and control brains. Incubation of control cortical membranes with 10 μM of serotonin in the presence of [35S] GTPγS increased [35S] GTP γS binding to membrane Gαo, Gαi, Gαq and Gαs proteins. This receptor-mediated activation of the Gα proteins was enhanced in cortical membranes obtained from bipolar brains. Immunoblot analyses revealed elevated concentration of Gαs but no alteration in the levels of the other Gα proteins or of Gβ in bipolar tissue. Evidence for increased receptor/G protein coupling in brain tissue of bipolar illness subjects was also obtained in studies in which serotonin-induced dissociation of the heterotrimeric G proteins was assessed. In addition, platelets from bipolar subjects and membranes of bipolar brains exhibited increased levels of PKC activity and enhanced translocation of the enzyme from cytosol to the membrane in response to serotonin receptor stimulation or direct PKC activation with phorbol ester. These results suggest that the coupling of the serotonin receptors to their associated G proteins and the subsequent translocation of PKC to the membrane are enhanced in bipolar brains and may contribute to the pathophysiology of the disorder. Supported by USPHS Grant MH40380.