Beta-amyloid peptide stimulates endozepine release in cultured rat astrocytes through activation of N-formyl peptide receptors.
Astroglial cells synthesize and release endozepines, a family of neuropeptides derived from diazepam-binding inhibitor (DBI). The authors have recently shown that beta-amyloid peptide (Abeta) stimulates DBI gene expression and endozepine release. The purpose of this study was to determine the mechanism of action of Abeta in cultured rat astrocytes. Abeta(25-35) and the N-formyl peptide receptor (FPR) agonist N-formyl-Met-Leu-Phe (fMLF) increased the secretion of endozepines in a dose-dependent manner with EC(50) value of approximately 2 microM. The stimulatory effects of Abeta(25-35) and the FPR agonists fMLF and N-formyl-Met-Met-Met (fMMM) on endozepine release were abrogated by the FPR antagonist N-t-Boc-Phe-Leu-Phe-Leu-Phe. In contrast, Abeta(25-35) increased DBI mRNA expression through a FPR-independent mechanism. Abeta(25-35) induced a transient stimulation of cAMP formation and a sustained activation of polyphosphoinositide turnover. The stimulatory effect of Abeta(25-35) on endozepine release was blocked by the adenylyl cyclase inhibitor somatostatin, the protein kinase A (PKA) inhibitor H89, the phospholipase C inhibitor U73122, the protein kinase C (PKC) inhibitor chelerythrine and the ATP binding cassette transporter blocker glyburide. Taken together, these data demonstrate for the first time that Abeta(25-35) stimulates endozepine release from rat astrocytes through a FPR receptor positively coupled to PKA and PKC.
Tokay
Tursonjan
T
INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, University of Rouen, Mont-Saint-Aignan, France.
Hachem
Raya
R
Masmoudi-Kouki
Olfa
O
Gandolfo
Pierrick
P
Desrues
Laurence
L
Leprince
Jerome
J
Castel
Helene
H
Diallo
Mickael
M
Amri
Mohamed
M
Vaudry
Hubert
H
Tonon
Marie-Christine
MC
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D026261:Diazepam Binding Inhibitor / Q000378:metabolism*; D009479:Neuropeptides / Q000502:physiology; D010446:Peptide Fragments / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020239:Receptor Cross-Talk / Q000502:physiology; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D026261:Diazepam Binding Inhibitor; D009479:Neuropeptides; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; C074636:amyloid beta-protein (25-35); C067529:diazepam binding inhibitor (33-50); D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C