Inhibitors of CDP-choline synthesis, action potential calcium channels, and stimulus-secretion coupling.
The effects of putative transmethylation inhibitors were tested on stimulus-secretion coupling and neurotransmitter secretion at synapses between neuroblastoma X glioma hybrid cells and myotubes. 5'-Deoxy-5'-isobutylthio-3-deazaadenosine or 5'-deoxy-5'-isobutylthioadenosine inhibited CDP-choline synthesis catalyzed by cholinephosphate cytidylyltransferase (CTP:cholinephosphate cytidylyltransferase, EC 2.7.7.15) and thereby decreased the rate of phosphatidylcholine synthesis from CDP-choline, but did not affect the transmethylation pathway for phosphatidylcholine synthesis. These compounds also inhibited 45Ca2+ uptake by hybrid cells mediated by voltage-sensitive Ca2+ channels, acetylcholine secretion at synapses, and signal transduction through cell membranes mediated by myotube nicotinic acetylcholine receptors. In contrast, 3-deazaadenosine or adenosine inhibited the transmethylation pathway for phosphatidylcholine synthesis, but had no effect on Ca2+ action potentials, acetylcholine secretion, or signal transduction through cell membranes mediated by nicotinic acetylcholine receptors. These results show that the stimulus-secretion coupling and secretion reactions studied are not dependent on phospholipid methylation and suggest that the activity of action potential Ca2+ channels and the rate of neurotransmitter secretion are functionally coupled to the rate of phosphatidylcholine synthesis via the CDP-choline pathway.
D000109:Acetylcholine / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002794:Choline / Q000031:analogs & derivatives*; D019916:Choline-Phosphate Cytidylyltransferase; D003566:Cytidine Diphosphate Choline / Q000096:biosynthesis*; D003839:Deoxyadenosines / Q000031:analogs & derivatives / Q000494:pharmacology; D006822:Hybrid Cells / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects*; D051379:Mice; D009045:Motor Endplate / Q000187:drug effects; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors; D010713:Phosphatidylcholines / Q000096:biosynthesis; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D013872:Thionucleosides / Q000494:pharmacology; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology
D003839:Deoxyadenosines; D007473:Ion Channels; D010713:Phosphatidylcholines; D011978:Receptors, Nicotinic; D013872:Thionucleosides; C018258:3-deazaadenosine; C013919:5'-deoxy-5'-S-isobutylthioadenosine; D003566:Cytidine Diphosphate Choline; C017194:5'-deoxy-5'-(isobutylthio)-3-deazaadenosine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D009713:Nucleotidyltransferases; D019916:Choline-Phosphate Cytidylyltransferase; D014372:Tubercidin; D002794:Choline; D000109:Acetylcholine; D002118:Calcium