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

Eitan Friedman, Hoau Yan Wang

Research output: Contribution to journalArticlepeer-review

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]GTPγS) binding to specific G(α) proteins in a receptor-selective manner. The abilities of these receptor agonists to stimulate the binding of [35S]GTPγS to the G(α) proteins was enhanced in membranes from bipolar brains. Immunoblot analyses showed increases in the levels of membrane 45- and 52-kDa G(αs) proteins but no changes in the amounts of G(αi), G(αo), G(αz), G(αq/11), or G(β) proteins in membrane or cytosol fractions of bipolar brain homogenates. Pertussis toxin (PTX)- activated ADP-ribosylations of G(αi) and G(αo) were enhanced by ~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(αi)/G(αo) 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(α) proteins that coimmunoprecipitated with the G(α) 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.

Original languageEnglish
Pages (from-to)1145-1152
Number of pages8
JournalJournal of Neurochemistry
Volume67
Issue number3
DOIs
StatePublished - Sep 1996
Externally publishedYes

Keywords

  • Bipolar affective disorder
  • G proteins
  • Receptor-mediated activation

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