The N-terminal tripeptide of insulin-like growth factor-I protects against beta-amyloid-induced somatostatin depletion by calcium and glycogen synthase kinase 3 beta modulation.
The protective effects of insulin-like growth factor I on the somatostatin (SRIF) system in the temporal cortex after beta-amyloid (Abeta) injury may be mediated through its N-terminal tripeptide glycine-proline-glutamate (GPE). GPE is cleaved to cyclo[Pro-Gly] (cPG), a metabolite suggested to mediate in neuroprotective actions. We evaluated the effects of GPE and cPG in the temporal cortex of Abeta25-35-treated rats on SRIF and SRIF receptor protein and mRNA levels, adenylyl cyclase activity, cell death, Abeta25-35 accumulation, cytosolic calcium levels ([Ca(2+)](c)) and the intracellular signaling mechanisms involved. GPE and cPG did not change Abeta25-35 levels, but GPE partially restored SRIF and SRIF receptor 2 protein content and mRNA levels and protected against cell death after Abeta25-35 insult, which was coincident with Akt activation and glycogen synthase kinase 3beta inhibition. In addition, GPE displaced glutamate from NMDA receptors and blocked the glutamate induced rise in cytosolic calcium in isolated rat neurons and moderately increased Ca(2+) influx per se. Our findings suggest that GPE, but not its metabolite, mimics insulin-like growth factor I effects on the SRIF system through a mechanism independent of Abeta clearance that involves modulation of calcium and glycogen synthase kinase 3beta signaling.
Burgos-Ramos
Emma
E
Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
Martos-Moreno
Gabriel A
GA
López
Manuela G
MG
Herranz
Rosario
R
Aguado-Llera
David
D
Egea
Javier
J
Frechilla
Diana
D
Cenarruzabeitia
Edurne
E
León
Rafael
R
Arilla-Ferreiro
Eduardo
E
Argente
Jesús
J
Barrios
Vicente
V
D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D007334:Insulin-Like Growth Factor I / Q000737:chemistry / Q000502:physiology*; D009842:Oligopeptides / Q000502:physiology*; D010446:Peptide Fragments / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D013004:Somatostatin / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C062053:glycyl-prolyl-glutamic acid