Inhibition of carbachol-stimulated phosphoinositide turnover by U-50,488H in rat hippocampus--involvement of GTP-binding protein.
The effect of U-50,488H, a selective kappa-opioid agonist, on carbachol-stimulated phosphoinositide (PI) turnover response in rat hippocampal slices was examined. U-50,488H which stimulates PI turnover response in this preparation (Periyasamy and Hoss, 1990, Life Sci. 47, 219), inhibited carbachol-stimulated PI turnover in a concentration-dependent manner with an IC50 value of 33 +/- 9.0 microM. The inhibitory effect of U-50,488H was not blocked by the kappa-selective antagonists, e.g., nor-binaltorphimine (10 microM), and MR2266 (10 microM), or tetrodotoxin (1 microM) suggesting that the effect of U-50,488H was mediated neither through the kappa-receptors nor through the release of an endogenous neurotransmitter(s). A Lineweaver-Burke plot of the stimulation of PI turnover by carbachol in the presence and absence of U-50,488H showed that the Km was not changed (11.4 +/- 3.4 and 11.5 +/- 2.6 microM) whereas the Vmax was reduced from 3849 +/- 460 to 1534 +/- 31 cpm indicating that the inhibition was non-competitive. U-50,488H also inhibited guanosine 5'-[beta, gamma-imido]triphosphate (Gpp[NH]p)-stimulated PI turnover in rat hippocampal membranes in a concentration-dependent manner with an IC50 value of 33 +/- 12 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
Periyasamy
S
S
Department of Medicinal and Biological Chemistry, University of Toledo, College of Pharmacy, OH 43606.
Hoss
W
W
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects*; D007051:Ibotenic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium; D010738:Type C Phospholipases / Q000494:pharmacology
D010716:Phosphatidylinositols; D011759:Pyrrolidines; D014316:Tritium; D007051:Ibotenic Acid; D012701:Serotonin; D013779:Tetrodotoxin; D011813:Quinuclidinyl Benzilate; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D002217:Carbachol; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D009638:Norepinephrine