Effects of T-588, a novel cognitive enhancer, on ADP-ribosylation of G(s alpha) by cholera toxin and cyclic AMP accumulation in rat cerebral cortex.
We investigated the effects of R(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy]ethan ol hydrochloride (T-588), a novel cognitive enhancer, on trimeric GTP-binding proteins (G proteins) and cyclic AMP accumulation in rat cerebral cortex. T-588 (0.1-1.0 mM) inhibited the ADP-ribosylation of alpha subunit of Gs in a concentration-dependent manner. Auto-ADP-ribosylation of CTX was not inhibited by T-588. The stimulatory effect of guanosine 5'-(3-O-thio)triphosphate (GTPgammaS) on CTX-catalyzed ADP-ribosylation was attenuated by adding T-588 in assay mixture. ADP-ribosylation of Gi/Go by pertussis toxin was slightly inhibited by T-588. Isoproterenol-stimulated cyclic AMP accumulation was inhibited by adding 3 mM T-588 to rat cerebral cortical slices. Next, we investigated the effects of isoproterenol and T-588 on GTPgammaS binding. Membranes were first incubated with or without isoproterenol and T-588 in the presence of 0.2mM GTPgammaS, then cholate extract preparations were prepared from the washed membranes. Interestingly, the [32P]ADP-ribosylation of G(s alpha) was enhanced not only by isoproterenol but also by T-588. Although the obtained results are apparently inconsistent, T-588 seems to interact with G proteins, specifically Gs.
Maekawa
M
M
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Miyazaki
H
H
Ono
S
S
Narita
H
H
Murayama
T
T
Nomura
Y
Y
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002772:Cholera Toxin / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D004048:Diethylamines / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology; D037342:Pertussis Toxin; D010761:Phosphorus Radioisotopes; D051381:Rats; D013876:Thiophenes / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D004048:Diethylamines; D018697:Nootropic Agents; D010761:Phosphorus Radioisotopes; D013876:Thiophenes; D010566:Virulence Factors, Bordetella; C082372:T 588; D000246:Adenosine Diphosphate Ribose; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000262:Adenylyl Cyclases; D007545:Isoproterenol