title: Receptor-mediated activation of G proteins is increased in postmortem brains of bipolar affective disorder subjects.
abstract: Guanine nucleotide binding proteins (G proteins) have been implicated in the pathophysiology of bipolar affective disorder. In the present investigation receptor-mediated G protein activation and changes in G protein trimeric state were examined in frontal cortical membranes obtained from postmortem brains of bipolar affective disorder subjects and from age-, sex-, and postmortem interval-matched controls. Stimulation of cortical membranes with serotonin, isoproterenol, or carbachol increased guanosine 5'-O-(3-[35S]thiophosphate) ([35S]GTP gamma S) binding to specific G alpha proteins in a receptor-selective manner. The abilities of these receptor agonists to stimulate the binding of [35S]GTP gamma S to the G alpha proteins was enhanced in membranes from bipolar brains. Immunoblot analyses showed increases in the levels of membrane 45- and 52-kDa G alpha S proteins but no changes in the amounts of G alpha i, G alpha o, G alpha Z, G alpha q/11, or G beta proteins in membrane or cytosol fractions of bipolar brain homogenates. Pertussis toxin (PTX)-activated ADP-ribosylations of G alpha i and G alpha o were enhanced by approximately 80% in membranes from bipolar compared with control brains, suggesting an increase in the levels of the trimeric state of these G proteins in bipolar disorder. Serotonin-induced, magnesium-dependent reduction in PTX-mediated ADP-ribosylation of G alpha i/G alpha o in cortical membranes from bipolar brains was greater than that observed in controls, providing further evidence for enhanced receptor-G protein coupling in bipolar brain membranes. In addition, the amounts of G beta proteins that coimmunoprecipitated with the G alpha proteins were also elevated in bipolar brains. The data show that in bipolar brain membrane there is enhanced receptor-G protein coupling and an increase in the trimeric state of the G proteins. These changes may contribute to produce exaggerated transmembrane signaling and to the alterations in affect that characterize bipolar affective disorder.
authors: Department of Pharmacology, Medical College of Pennsylvania, Philadelphia 19129, USA.
authors: E
authors: E
authors: Friedman
authors: H Y
authors: HY
authors: Wang
mesh_terms: D000262:Adenylyl Cyclases; D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D001345:Autoradiography; D001714:Bipolar Disorder / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology*; D005260:Female; D005625:Frontal Lobe / Q000737:chemistry / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D010761:Phosphorus Radioisotopes; D011233:Precipitin Tests; D011956:Receptors, Cell Surface / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013462:Sulfur Radioisotopes
chemical_list: D008565:Membrane Proteins; D010761:Phosphorus Radioisotopes; D011956:Receptors, Cell Surface; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013462:Sulfur Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases