Gangliosides as modulators of the coupling of neurotransmitters to adenylate cyclase.
Cultured NCB-20 mouse neuroblastoma X Chinese hamster brain clonal hybrid cells express an adenylate cyclase-coupled receptor for serotonin (5HT) which corresponds pharmacologically to the 5HT1 receptor in whole brain, except for its much lower affinity for serotonin. Studies showed that the affinity of the NCB-20 receptor could be increased to near that of the whole brain receptor and the potency of 5HT in elevating cyclic AMP levels increased by pre-incubating NCB-20 cells for at least 3 hours with submicromolar concentrations of brain gangliosides. Tetrasialoganglioside (GQ1b) was found to be the most potent ganglioside tested, producing a ten-fold increase in affinity. However, the actual 5HT binding site is a protein and we have obtained no evidence that serotonin binds directly to gangliosides at the concentrations at which it labels the receptor. The receptor-mediated inhibition of adenylate cyclase by biogenic amines such as dopamine and clonidine through dopamine (D2) and alpha-adrenoreceptors was unaffected by pre-incubation of the NCB-20 cells with gangliosides. Enkephalin was also found to acutely supress both the ability of 5HT to stimulate adenylate cyclase activity and the synthesis of polysialogangliosides in NCB-20 cells. After 6 hours of exposure, the cells became tolerant to enkephalin and after 36 hours the cells became supersensitive to 5HT in terms of adenylate cyclase activation and 5HT binding. The affinity of the receptor for 5HT increased the same 10-fold magnitude as achieved by GQ1b pre-incubation in comparison with untreated cells. This increase in receptor affinity appeared to coincide chronologically with the increase in ganglioside synthesis observed in enkephalin tolerant cells, further suggesting an important role of polysialogangliosides in the function of the serotonin (5HT1) receptor.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000502:physiology; D002460:Cell Line; D003000:Clonidine / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D005732:Gangliosides / Q000096:biosynthesis / Q000502:physiology*; D006822:Hybrid Cells / Q000502:physiology; D007700:Kinetics; D051379:Mice; D009447:Neuroblastoma / Q000503:physiopathology; D009474:Neurons / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism
D005732:Gangliosides; D018377:Neurotransmitter Agents; D011985:Receptors, Serotonin; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D000262:Adenylyl Cyclases; D003000:Clonidine