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Guanine Nucleotide-Binding Proteins in Bipolar Affective Disorder:  Effects of Long-term Lithium Treatment

Husseini K. Manji, MD, FRCPC; Guang Chen, MD; Hady Shimon; John K. Hsiao, MD; William Z. Potter, MD, PhD; Robert H. Belmaker, MD
Arch Gen Psychiatry. 1995;52(2):135-144. doi:10.1001/archpsyc.1995.03950140053007.
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Background:  This study examines recent suggestions from a number of investigators that signal-transducing guanine nucleotide-binding (G) proteins may be involved in the pathophysiology of bipolar affective disorder and may represent molecular targets for lithium's mood-stabilizing actions.

Methods:  We used selective antibodies to quantitate the levels of the G protein α subunits that regulate adenylate cyclase activity (Gαs and Gαi2) and phosphoinositide turnover (Gαq/11). We also quantitated levels of pertussis toxin—catalyzed phosphate 32—labeled adenosine diphosphate ([32P] ADP) ribosylation in platelet and leukocyte membranes from a group of 14 untreated (predominantly manic) patients with bipolar affective disorder, 20 lithium-treated euthymic patients with bipolar affective disorder, and 11 healthy controls.

Results:  In both tissues, the immunolabeling of the 45-kd form of Gαs was higher in the bipolar affective disorder group considered as a whole (treated or untreated) compared with controls, effects that reached statistical significance in the leukocyte membranes. There were no significant differences in the immunolabeling of Gαi2/2, Gαq/11, or pertussis toxin—catalyzed [32P]ADP ribosylation in either tissue in the untreated bipolar affective disorder group compared with controls. In both tissues, lithium-treated subjects demonstrated lower levels of Gαq/11 and higher levels of pertussis toxin—catalyzed [32P]ADP-ribosylation, which reached significance in the platelet membranes.

Conclusions:  Our results are complementary to the previously reported findings of elevated Gαs levels in postmortem brain tissue from patients with bipolar affective disorder and in mononuclear leukocytes obtained from depressed patients with bipolar (but not unipolar) affective disorder. The significantly higher levels of pertussis toxin—catalyzed [32P] ADP ribosylation in the subjects receiving long-term lithium-treatment replicates our findings in rat cortex and in healthy volunteers and adds to the growing body of evidence implicating Gαi as a target of lithium's actions.

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