Melatonin receptor-mediated stimulation of phosphoinositide breakdown in chick brain slices.
The direct effect of melatonin and related agonists on Li(+)-amplified phosphoinositide breakdown was studied in chick brain slices prelabeled with myo-[2-3H]-inositol. The melatonin receptor agonist 6-chloromelatonin (10-100 microM) increased, in a concentration-dependent manner, the accumulation of inositol phosphates (IP) in chick brain slices. This effect of 6-chloromelatonin (10 microM) was rapid as transient increases in IP3/IP4 (maximal increase, 29% at 20 s) and IP2 levels (maximal increase, 36% at 1 min) were observed, followed by a slower but sustained increase in IP1 level (30% at 5 min), when the amount of IP3/IP4 and IP2 had already been decreased to the control level. The phosphoinositide response elicited by 6-chloromelatonin (10 microM) was dependent on the presence of extracellular calcium. Direct stimulation of membrane phospholipase C by 6-chloromelatonin (10 microM) in isolated myo-[2-3H]inositol-prelabeled optic tectum membranes was dependent on the presence of guanosine-5'-O-(3-thio)triphosphate (1 microM), thus suggesting that G protein(s) link melatonin receptor activation to phospholipase C stimulation. The competitive melatonin receptor antagonist luzindole (10-100 microM) inhibited in a concentration-dependent manner the IP1 accumulation stimulated by 6-chloromelatonin (10-100 microM); however, it did not affect the accumulation stimulated by 5-hydroxytryptamine (10 microM). By contrast, methysergide (10 microM) completely inhibited 5-hydroxy-tryptamine (10 microM)-, but not 6-chloromelatonin (10 microM)-, induced IP1 accumulation. Melatonin receptor agonists increased IP1 accumulation in a concentration-dependent manner reaching different maximal responses.(ABSTRACT TRUNCATED AT 250 WORDS)
Popova
J S
JS
Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois 60611.
Dubocovich
M L
ML
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D002645:Chickens / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D008550:Melatonin / Q000031:analogs & derivatives / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D044094:Receptors, Melatonin; D011985:Receptors, Serotonin / Q000502:physiology; D013997:Time Factors; D010738:Type C Phospholipases / Q000502:physiology
D010716:Phosphatidylinositols; D011956:Receptors, Cell Surface; D044094:Receptors, Melatonin; D011985:Receptors, Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C024100:6-chloromelatonin; D010738:Type C Phospholipases; D008550:Melatonin; D002118:Calcium