Receptor-mediated activation of G proteins is increased in postmortem brains of bipolar affective disorder subjects.
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.
Friedman
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Department of Pharmacology, Medical College of Pennsylvania, Philadelphia 19129, USA.
Wang
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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
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