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Keywords:

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

Abstract

  1. Top of page
  2. Abstract

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 m1 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, p21ras, 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.

Abbreviations used: Aβ, amyloid β-protein; APP, amyloid precursor protein; APPs, soluble form of amyloid precursor protein; bFGF, basic fibroblast growth factor; CCh, carbachol; ERK, extracellular signal-regulated kinase; FTS, S-trans,trans-farnesylthiosalicylic acid; mAChR, muscarinic acetylcholine receptor; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; MEK, mitogen-activated protein kinase kinase; NGF, nerve growth factor; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; RTK, receptor tyrosine kinase; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TBM, 3,3′,5,5′-tetramethylbenzidine.