Vinconate, a cognitive enhancer, and PI turnover-phospholipase C systems in the brain.
The molecular mechanisms for the stimulation of inositol 1-phosphate (IP1) formation by vinconate were investigated using preparations of rat brain. Vinconate (10(-8)-10(-3) M) dose-dependently inhibited the binding of [3H]quinuclidinyl benzilate ([3H]QNB) to muscarinic acetylcholine receptors and its IC50 value for [3H]QNB binding was 1.7 x 10(-5) M. The rightward shift of carbachol displacement curve of [3H]QNB binding by GTP (10(-4) M) was completely abolished by vinconate (10(-5) M). Carbachol (10(-8)-10(-2) M) increased [3H]IP1 formation in a dose-dependent manner and the carbachol-induced [3H]IP1 formation was significantly accentuated by vinconate (10(-5) M). The enhancement of [3H]IP1 accumulation by vinconate was inhibited by approximately 50% in the presence of atropine (10(-5) M), although phentolamine and ketanserin had no effects on the stimulatory effect of vinconate on [3H]IP1 formation. Vinconate showed no alteration in the binding of [3H]guanosine 5'-(beta, gamma-imino) triphosphate ([3H]Gpp(NH)p) to the crude synaptic membranes. The enhancement of phosphatidylinositol 4,5-biphosphate (PIP2)-specific phospholipase C (PLC) activity by GTP was unaffected in the presence of 10(-3) M vinconate, whereas vinconate alone dose-dependently enhanced the activities of both PIP2-specific and cytosolic PLC. These results suggest that vinconate may induce the facilitation of phosphatidylinositide (PI) turnover via the stimulation of muscarinic acetylcholine receptors, the enhancement of coupling between muscarinic acetylcholine receptors and GTP-binding protein, and the direct activations of PIP2-specific and cytosolic PLC.
Katsura
M
M
Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
Iino
T
T
Xu
J
J
Ohkuma
S
S
Kuriyama
K
K
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D006165:Guanylyl Imidodiphosphate / Q000378:metabolism; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism*; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010276:Parasympatholytics / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism*; D014748:Vinca Alkaloids / Q000494:pharmacology*
D007295:Inositol Phosphates; D018727:Muscarinic Antagonists; D009419:Nerve Tissue Proteins; D010276:Parasympatholytics; D010277:Parasympathomimetics; D014748:Vinca Alkaloids; C002647:inositol 1-phosphate; D006165:Guanylyl Imidodiphosphate; C038627:vinconate; D010738:Type C Phospholipases