Discrete activation of transduction pathways associated with acetylcholine m1 receptor by several muscarinic ligands

David Gurwitz, Rachel Haring, Eliahu Heldman, Claire M. Fraser, David Manor, Abraham Fisher

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

Activation of transfected muscarinic m1 acetylcholine receptors (m1AChR) has been linked to several signal transduction pathways which include phosphoinositide hydrolysis, arachidonic acid release and cAMP accumulation. In Chinese hamster ovary cells stably transfected with the rat m1AChR gene, carbachol elicited all three responses with EC50 values of 2.6, 3.8 and 76 μM, respectively. However, pilocarpine and the selective muscarinic agonist AF102B activated phosphoinositide hydrolysis (by 94 and 27% vs. carbachol, respectively), while antagonizing carbachol-mediated cAMP accumulation. Carbachol also activated (by 4-fold) adenylyl cyclase in membranes prepared from these cells, indicating independence of this signal from intracellular mediators. Moreover, carbachol and AF102B similarly elevated cytosolic Ca2+ in intact m1AChR-transfected cells. The ligand-selective cAMP accumulation, its independence from Ca2+ and the carbachol-activated adenylyl cyclase in membranes suggest that it represents an independent m1AChR-mediated signal, unrelated to phosphoinositide hydrolysis. Selective muscarinic ligands such as AF102B may independently activate distinct signalling pathways, which may be important for designing cholinergic replacement therapy for treating Alzheimer's disease.

Original languageEnglish
Pages (from-to)21-31
Number of pages11
JournalEuropean Journal of Pharmacology: Molecular Pharmacology
Volume267
Issue number1
DOIs
StatePublished - 15 Mar 1994
Externally publishedYes

Keywords

  • AF102B
  • Arachidonic acid
  • Ca imaging
  • G protein
  • Phosphoinositide
  • cAMP

ASJC Scopus subject areas

  • Pharmacology

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