ALTERATIONS IN CYCLIC-AMP GENERATION AND G-PROTEIN SUBUNITS FOLLOWINGTRANSIENT ISCHEMIA IN GERBIL HIPPOCAMPUS

We examined alterations in the cyclic AMP generating system and G prot ein subunits in gerbil hippocampus following 10 min of transient ische mia, In hippocampal slices, basal and isoproterenol- and forskolin-sti mulated cyclic AMP accumulations were markedly increased at 6 and 24 h after ischemia. Interestingly, both the inhibition of forskolin-stimu lated cyclic AMP and the potentiation of beta-adrenoceptor-stimulated cyclic AMP by a gamma-aminobutyric acid, receptor agonist were attenua ted at these time points. Ischemia did not affect the immuno-labeling of any of the G protein or subunits; only that of beta subunits was si gnificantly decreased, by 28.2%, 4 days after ischemia. In contrast, p ertussis toxin-catalyzed [P-32]ADP ribosylation declined progressively during the late recirculation period, reaching a significant reductio n (25.4%) at 6 h after ischemia. These results suggest that ischemia a ffects the heterotrimeric conformation (alpha beta gamma) of G(i)/G(o) during the recirculation period, thereby leading to increased cyclic AMP production. Because cyclic AMP-dependent protein kinase A modulate s the lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-kainate receptor channels, postischemic sensitization of the cyclic AMP genera ting system may contribute to neuronal degeneration in the hippocampus .