Mitogen‐Activated Protein Kinase‐Dependent and Protein Kinase C‐Dependent Pathways Link the m1 Muscarinic Receptor to β‐Amyloid Precursor Protein Secretion
Mitogen‐Activated Protein Kinase‐Dependent and Protein Kinase C‐Dependent Pathways Link the m1 Muscarinic Receptor to β‐Amyloid Precursor Protein Secretion
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DOI：
10.1046/j.1471-4159.1998.71052094.x
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发表时间：
1998-11
影响因子：
4.7
通讯作者：
R. Haring;A. Fisher;D. Marciano;Z. Pittel;Y. Kloog;Avi Zuckerman;N. Eshhar;E. Heldman
中科院分区：
文献类型：
--
作者：
R. Haring;A. Fisher;D. Marciano;Z. Pittel;Y. Kloog;Avi Zuckerman;N. Eshhar;E. Heldman
摘要：完全和功能选择性M1毒蕈碱激动剂（分别为卡巴胆碱和AF 102 B）激活表达m1毒蕈碱受体的PC 12细胞（PC 12 M1细胞）中可溶性淀粉样前体蛋白（APP）的分泌。神经营养因子如神经生长因子和碱性成纤维细胞生长因子进一步增强了这种激活。毒蕈碱刺激激活导致APP分泌的两种转导途径：蛋白激酶C（PKC）依赖性和丝裂原活化蛋白激酶（MAPK）依赖性途径。这些途径平行运作，并与神经营养因子的转导途径汇合，从而导致毒蕈碱激动剂和神经营养因子刺激PC 12 M1细胞时APPs分泌的增强。这些结论得到以下结果的支持：（a）当PKC、p21 ras或MAPK被其各自的特异性抑制剂GF 109203 X、S-反式、反式法尼基硫代水杨酸和PD 98059完全抑制时，仅观察到部分阻断APP分泌。(b)K252 a阻断PKC和佛波醇12-肉豆蔻酸酯13-乙酸酯诱导的APP分泌，增强毒蕈碱刺激的MAPK活化和APP分泌。(c)毒蕈碱激动剂对PC 12 M1细胞中MAPK的激活是Ras依赖性的，但不依赖于PKC，并且通过神经营养因子协同增强。这些结果表明，毒蕈碱刺激APPs分泌介导的至少两个独立的途径，收敛和增强信号的APPs分泌的收敛点。
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.