M1, M3 and M5 muscarinic receptors stimulate mitogen-activated protein kinase.
We report here that the M1, M3 and M5 muscarinic acetylcholine receptor subtypes that have been shown to couple to phosphoinositide hydrolysis also activate the mitogen-activated protein kinase (MAPK). Pharmacological characterization as well as mechanistic details of the activation pathway are presented. Carbachol-induced MAPK activation was time- and concentration-dependent at all subtypes. Pharmacological characterization of the MAPK response revealed that McN-A-343 was a partial agonist at the M1 and M3 subtypes, and that pilocarpine was a partial agonist at the M3 and M5 receptors. Carbachol-mediated MAPK activation at these receptor subtypes was pertussis toxin and wortmannin insensitive. By contrast, both agents significantly inhibited carbachol-induced MAPK activation by the M2 muscarinic receptor subtype. Furthermore, two independent single point mutations in the M1 receptor attenuated carbachol-induced activation of MAPK. Activation of MAPK at the M1, M3 and M5 muscarinic receptor subtypes was not dependent on intracellular or extracellular Ca2+, but was partially dependent upon protein kinase C. These data suggest that activation of MAPK by M1, M3 and M5 muscarinic receptors involves protein kinase C-dependent and independent pathways.
Wotta
D R
DR
Division of Neuroscience Research in Psychiatry, Medical School, University of Minnesota, Minneapolis, USA.
Wattenberg
E V
EV
Langason
R B
RB
el-Fakahany
E E
EE
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D018721:Muscarinic Agonists / Q000494:pharmacology*; D037342:Pertussis Toxin; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D043642:Receptor, Muscarinic M5; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D043642:Receptor, Muscarinic M5; D011976:Receptors, Muscarinic; D012702:Serotonin Antagonists; D010566:Virulence Factors, Bordetella; D010862:Pilocarpine; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D002217:Carbachol; D037342:Pertussis Toxin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium; D000077191:Wortmannin