Signalling of the M3-muscarinic receptor to the anti-apoptotic pathway.
The process of programmed cell death (or apoptosis) occurs widely in tissue maintenance and embryonic development, and is under tight regulatory control. It is now clear that one of the important regulators of apoptosis are G-protein-coupled receptors. In the present study, we investigate the regulatory mechanism employed by the Gq/11-coupled M3-muscarinic receptor in mediating an anti-apoptotic response. Using a CHO (Chinese-hamster ovary) cell model, we demonstrate that the M3-muscarinic receptor anti-apoptotic response is independent of calcium/phospholipase C signalling. This response can, however, be inhibited by the transcriptional inhibitor actinomycin D at a concentration that inhibits the rapid increase in gene transcription mediated by M3-muscarinic receptor stimulation. Furthermore, apoptosis in CHO cells induced by the DNA-damaging agent, etoposide, is associated with a fall in the levels of the anti-apoptotic Bcl-2 protein. This fall in Bcl-2 protein concentration can be attenuated by M3-muscarinic receptor stimulation. We conclude, therefore, that the M3-muscarinic receptor signals to the anti-apoptotic pathway via a mechanism that is independent of calcium/phospholipase C signalling, but in a manner that involves both gene transcription and the up-regulation of Bcl-2 protein.
Budd
David C
DC
Department of Cell Physiology and Pharmacology, University of Leicester, P.O. Box 138, University Road, Leicester LE1 9HN, UK.
Spragg
Elizabeth J
EJ
Ridd
Katie
K
Tobin
Andrew B
AB
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016466:CHO Cells / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D007295:Inositol Phosphates; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D014316:Tritium; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D007295:Inositol Phosphates; D019253:Proto-Oncogene Proteins c-bcl-2; D043587:Receptor, Muscarinic M3; D043562:Receptors, G-Protein-Coupled; D014316:Tritium; D010738:Type C Phospholipases; D002118:Calcium