Stimulation of noradrenaline release by T-588, a cognitive enhancer, in PC12 cells.
Previously, we reported that (R)-(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N- diethylamino)ethoxy] ethanol hydrochloride (T-588), a novel putative cognitive enhancer, stimulated noradrenaline (NA) release from rat cerebral cortical slices. In this study, we investigated the effects of T-588 compared to other secretagogues on NA release from PC12 cells. Addition of as little as 10 microM T-588 stimulated [3H]NA release in a dose-dependent and an extracellular Ca(2+)-independent manner from PC12 cells. Ten micromolar ionomycin-, 300 microM adenosine-5'-O-(gamma-thiotriphosphate)- and 10 microM forskolin-induced extracellular Ca(2+)-dependent [3H]-NA release was further enhanced by 30 microM T-588. Cytosolic synaptophysin and 25-kDa synaptosome-associated protein immunoreactivity was increased by addition of T-588 in a dose-dependent manner. Interestingly, increases in synaptic vesicle-related proteins triggered by T-588 had a 4-min lag time and were completely dependent on extracellular CaCl2. These findings suggest that T-588 stimulates NA release from PC12 cells in a Ca(2+)-independent manner. T-588 also induced the translocation of synaptic vesicles in a Ca(2+)-dependent manner.
Maekawa
M
M
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Ono
S
S
Narita
H
H
Murayama
T
T
Nomura
Y
Y
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D004048:Diethylamines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins / Q000032:analysis; D009638:Norepinephrine / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D013572:Synaptic Vesicles / Q000187:drug effects; D016708:Synaptophysin / Q000032:analysis; D050825:Synaptosomal-Associated Protein 25; D013876:Thiophenes / Q000494:pharmacology*
D000697:Central Nervous System Stimulants; D004048:Diethylamines; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C494210:Snap25 protein, rat; D016708:Synaptophysin; D050825:Synaptosomal-Associated Protein 25; D013876:Thiophenes; C082372:T 588; D002118:Calcium; D009638:Norepinephrine