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

Abstract

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
JournalPharmacology
Volume56
Issue number4
DOIs
StatePublished - Apr 1998

Keywords

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

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