Altered CTX‐catalyzed and endogenous [³²P]ADP‐ribosylation of stimulatory G protein α_s isoforms in postmortem bipolar affective disorder temporal cortex

Abstract

Reports of elevated Gs alpha subunit (alpha(s)) immunolabeling and cAMP-mediated hyper-functionality in autopsied cerebral cortical brain regions from bipolar affective disorder (BD) patients suggest signal transduction abnormalities occur in this disorder. Because covalent modification of alpha(s) can affect its turnover and levels, we determined whether CTX-catalyzed and endogenous [(32)P] adenosine diphosphate (ADP)-ribosylation of alpha(s) isoforms are altered in temporal and occipital cortical regions, which show elevated alpha(s) levels in BD as compared to nonpsychiatric subjects. Reduced CTX-catalyzed [(32)P]ADP-ribosylated alpha(s-S) and endogenous [(32)P]ADP-ribosylation of a 39-kDa alpha(s)-like protein were found in BD temporal cortex compared to controls. These findings suggest that clearance of these alpha(s) isoforms through ADP-ribosylation may be decreased in BD temporal cortex. Although no differences were observed in mean levels of endogenous and CTX-catalyzed [(32)P]ADP-ribosylation of alpha(s-L) in BD temporal cortex, alpha(s-L) immunolabeling was elevated significantly and correlated inversely with the degree of endogenous [(32)P]ADP-ribosylation of this subunit. In addition, endogenous [(32)P]ADP-ribosylation of an exogenous substrate, myelin basic protein, was similar in BD and comparison subject temporal cortex. Taken together, these observations suggest that elevations of alpha(s) in BD brain are more likely related to factors affecting the disposition or availability of alpha(s) to this posttranslational enzymatic modification.

The Concept of Dysregulated Signal Transduction and Gene Expression in the Pathophysiology of Mood Disorders

“…GTP-bound and the subunits become inactive after hydrolysis of GTP and re-association of GDP with and subunits. [32] reported reduced cholera toxin (CTX)-catalyzed adenosine diphosphate rybosylation of G s , which is an index of the post-translational process, in temporal cortex of bipolar patients, suggesting that elevation of G s in bipolar patients may be related to factors affecting disposition or availability of G s to post-translational enzymatic modifications.…”