MITOGEN-ACTIVATED PROTEIN KINASE-DEPENDENT AND PROTEIN-KINASE C-DEPENDENT PATHWAYS LINK THE M1 MUSCARINIC RECEPTOR TO BETA-AMYLOID PRECURSOR PROTEIN SECRETION

Full and functionally selective M1 muscarinic agonists (carbachol and AF102B, respectively) activate secretion of the soluble form of amyloi d precursor protein (APPs) in PC12 cells expressing the mi muscarinic receptor (PC12M1 cells). This activation is further augmented by neuro trophins such as nerve growth factor and basic fibroblast growth facto r. Muscarinic stimulation activates two transduction pathways that lea d to APPs secretion: protein kinase C (PKC)-dependent and mitogen-acti vated 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 agoni st and neurotrophins stimulate PC12M1 cells. These conclusions are sup ported by the following findings: (a) Only partial blockade of APPs se cretion is observed when PKC, p21(ras), or MAPK is fully inhibited by their respective specific inhibitors, GF109203X, S-trans,trans-farnesy lthiosalicylic acid, and PD98059. (b) K252a, which blocks PKC and phor bol 12-myristate 13-acetate-induced APPs secretion, enhances both musc arinic-stimulated MAPK activation and APPs secretion. (c) Activation o f MAPK in PC12M1 cells by muscarinic agonists is Ras-dependent but PKC -independent and is enhanced synergistically by neurotrophins. These r esults suggest that muscarinic stimulation of APPs secretion is mediat ed by at least two independent pathways that converge and enhance the signal for APPs secretion at the convergence point.