Mitogen-activated protein kinase-dependent and protein kinase C- dependent pathways link the m1 muscarinic receptor to β-amyloid precursor protein secretion

Rachel Haring, Abraham Fisher, Daniele Marciano, Zipora Pittel, Yoel Kloog, Avi Zuckerman, Nomi Eshhar, Eliahu Heldman

Research output: Contribution to journalArticlepeer-review

121 Scopus citations

Abstract

Full and functionally selective M1 muscarinic agonists (carbachol and AF102B, respectively) activate secretion of the soluble form of amyloid precursor protein (APPs) in PC12 cells expressing the ml muscarinic receptor (PC12M1 cells). This activation is further augmented by neurotrophins such as nerve growth factor and basic fibroblast growth factor. Muscarinic stimulation activates two transduction pathways that lead to APPs secretion: protein kinase C (PKC)-dependent and mitogen-activated protein kinase (MAPK)- dependent pathways. These pathways operate in parallel and converge with transduction pathways of neurotrophins, resulting in enhancement of APPs secretion when both muscarinic agonist and neurotrophins stimulate PC12M1 cells. These conclusions are supported by the following findings: (a) Only partial blockade of APPs secretion is observed when PKC, p21(ras), or MAPK is fully inhibited by their respective specific inhibitors, GF109203X, S-trans, trans-farnesylthiosalicylic acid, and PD98059. (b) K252a, which blocks PKC and phorbol 12-myristate 13-acetate-induced APPs secretion, enhances both muscarinic-stimulated MAPK activation and APPs secretion. (c) Activation of MAPK in PC12M1 cells by muscarinic agonists is Ras-dependent but PKC- independent and is enhanced synergistically by neurotrophins. These results suggest that muscarinic stimulation of APPs secretion is mediated by at least two independent pathways that converge and enhance the signal for APPs secretion at the convergence point.

Original languageEnglish
Pages (from-to)2094-2103
Number of pages10
JournalJournal of Neurochemistry
Volume71
Issue number5
DOIs
StatePublished - 1 Jan 1998
Externally publishedYes

Keywords

  • Alzheimer's amyloid precursor protein
  • Mitogen- activated protein kinase
  • Muscarinic acetylcholine receptor
  • Protein kinase C
  • Tyrosine kinase receptor
  • m1 agonists

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