Metabotropic Glutamate Receptor Subtype mGluR1α Stimulates the Secretion of the Amyloid β‐Protein Precursor Ectodomain

• Published in: Journal of neurochemistry Vol. 69; no. 2; pp. 704 - 712
• Main Authors: Nitsch, Roger M., Deng, Amy, Wurtman, Richard J., Growdon, John H.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.08.1997; Blackwell
• Subjects: Alzheimer's disease; Amyloid; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Medical sciences; Metabotropic glutamate receptor; Neurology; α‐Secretase processing; Nervous system diseases; Regulation(control); Cell line; Metabotropic receptor; Alzheimer disease; Central nervous system disease; Degenerative disease; Biosynthesis; Glutamate receptor; In vitro; Amyloid precursor protein; Cerebral disorder
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.1997.69020704.x

: To examine the effects of glutamatergic neurotransmission on amyloid processing, we stably expressed the metabotropic glutamate receptor subtype 1α (mGluR1α) in HEK 293 cells. Both glutamate and the selective metabotropic agonist 1‐amino‐1,3‐cyclopentanedicarboxylic acid (ACPD) rapidly increased phosphatidylinositol (PI) turnover four‐ to fivefold compared with control cells that were transfected with the expression vector alone. Increased PI turnover was effectively blocked by the metabotropic antagonist α‐methyl‐4‐carbophenylglycine (MCPG), indicating that heterologous expression of mGluR1α resulted in efficient coupling of the receptors to G protein and phospholipase C activation. Stimulation of mGluR1α with glutamate, quisqualate, or ACPD rapidly increased secretion of the APP ectodomain (APPs); these effects were blocked by MCPG. The metabotropic receptors were coupled to APP processing by protein kinases and by phospholipase A2 (PLA2), and melittin, a peptide that stimulates PLA2, potently increased APPs secretion. These data indicate that mGluR1α can be involved in the regulation of APP processing. Together with previous findings that muscarinic and serotonergic receptor subtypes can increase the secretion of the APP ectodomain, these observations support the concept that proteolytic processing of APP is under the control of several major neurotransmitters.