Receptor-mediated activation of G proteins is increased in postmortem brains of bipolar affective disorder subjects

J Neurochem. 1996 Sep;67(3):1145-52. doi: 10.1046/j.1471-4159.1996.67031145.x.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclases
  • Aged
  • Aged, 80 and over
  • Autopsy
  • Autoradiography
  • Bipolar Disorder / metabolism*
  • Brain Chemistry / physiology*
  • Female
  • Frontal Lobe / chemistry
  • Frontal Lobe / metabolism
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / metabolism*
  • Guanosine 5'-O-(3-Thiotriphosphate) / agonists
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology
  • Guanosine Triphosphate / agonists
  • Guanosine Triphosphate / metabolism
  • Guanosine Triphosphate / pharmacology
  • Humans
  • Immunoblotting
  • Male
  • Membrane Proteins / metabolism
  • Middle Aged
  • Phosphorus Radioisotopes
  • Precipitin Tests
  • Receptors, Cell Surface / metabolism
  • Receptors, Serotonin / metabolism
  • Serotonin Receptor Agonists / pharmacology
  • Sulfur Radioisotopes


  • Membrane Proteins
  • Phosphorus Radioisotopes
  • Receptors, Cell Surface
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • Sulfur Radioisotopes
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Guanosine Triphosphate
  • GTP-Binding Proteins
  • Adenylyl Cyclases