M3 muscarinic receptors promote cell survival through activation of the extracellular regulated kinase (ERK1/2) pathway.
Activation of certain subtypes of the muscarinic acetylcholine receptor can enhance cell survival. In SK-N-SH human neuroblastoma cells, muscarinic acetylcholine receptor activation induces phosphorylation of CREB and induction of EGR1, transcription factors associated with cell growth and survival. We identified the M3 muscarinic acetylcholine receptor subtype as being primarily responsible for these transcription factor responses after stimulation with carbachol, using subtype-preferring receptor antagonists and muscarinic snake toxins. In a cell survival/death model in SK-N-SH cells deprived of serum growth factors, carbachol increased cell viability, an effect blocked by the non-specific muscarinic antagonist atropine and the M3-preferring antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), suggesting that the M3 receptor is also driving the survival response in these cells. This cytoprotection is largely dependent on activation of the p44/42 extracellular regulated kinase (ERK1/2) pathway. Understanding such survival signalling pathways is important for both potential interventions in neurodegenerative disease and for targeting neuroblastoma and malignancies of the central nervous system.
Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. jeffrey.greenwood@plantandfood.co.nz
Jeffrey M
JM
Greenwood
Michael
M
Dragunow
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019610:Cytoprotection; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D017815:Elapidae; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D030162:Reptilian Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D017362:Cyclic AMP Response Element-Binding Protein; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D043587:Receptor, Muscarinic M3; D030162:Reptilian Proteins; D002217:Carbachol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3