TY - JOUR
T1 - Mitogen-activated protein kinase-dependent and protein kinase C- dependent pathways link the m1 muscarinic receptor to β-amyloid precursor protein secretion
AU - Haring, Rachel
AU - Fisher, Abraham
AU - Marciano, Daniele
AU - Pittel, Zipora
AU - Kloog, Yoel
AU - Zuckerman, Avi
AU - Eshhar, Nomi
AU - Heldman, Eliahu
PY - 1998/11
Y1 - 1998/11
N2 - 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.
AB - 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.
KW - Alzheimer's amyloid precursor protein
KW - Mitogen- activated protein kinase
KW - Muscarinic acetylcholine receptor
KW - Protein kinase C
KW - Tyrosine kinase receptor
KW - m1 agonists
UR - http://www.scopus.com/inward/record.url?scp=0031751761&partnerID=8YFLogxK
U2 - 10.1046/j.1471-4159.1998.71052094.x
DO - 10.1046/j.1471-4159.1998.71052094.x
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C2 - 9798935
AN - SCOPUS:0031751761
SN - 0022-3042
VL - 71
SP - 2094
EP - 2103
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 5
ER -