M1, M3 and M5 muscarinic receptors stimulate mitogen-activated protein kinase

Diane R. Wotta, Elizabeth V. Wattenberg, Rosemary B. Langason, Esam E. El-Fakahany

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)175-186
Number of pages12
Issue number4
StatePublished - Apr 1998


  • Calcium signaling
  • G proteins
  • Inhibitors
  • Mitogen-activated protein kinase
  • Muscarinic acetylcholine receptors
  • Mutant receptors
  • Receptor subtypes

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