Role of insulin-like growth factor binding proteins in limitation of IGF-I degradation into the N-methyl-D-aspartate receptor antagonist GPE: evidence from gonadotrophin-releasing hormone secretion in vitro at two developmental stages.
We showed previously that insulin-like growth factor-I (IGF-I) could inhibit the secretion of gonadotrophin-releasing hormone (GnRH) evoked in vitro by N-methyl-D-aspartate (NMDA) or veratridine depolarization. Such an IGF-I effect appeared to be mediated by its physiological breakdown product, the N-terminal tripeptide GPE. That effect was developmentally regulated since IGF-I could inhibit GnRH secretion from hypothalamic explants of 50-day-old adult rats but not from immature 15-day-old explants. We hypothesized that the IGF-binding proteins (BPs) could limit the peptide availability to endopeptidases and account for the absent IGF-I effects at 15 days. In this paper, we show that the inhibition of GnRH secretion by 10(-10) M of IGF-I at 50 days is prevented in a dose-dependent manner by 0.3 to 3 nM of IGF-BP2 as well as IGF-BP3. The inhibition caused by 10(-10) M of GPE is not affected under similar conditions. Using explants obtained at 15 days, a significant inhibition of GnRH secretion can be obtained by 10(-10) M of IGF-I in the presence of an anti IGF-BP2 antiserum used at 1:3000 and 1:1000 concentrations. These data indicate that in the immature rat brain, the IGF-BPs could act as modulators of IGF-I degradation into its subproduct GPE, a possible endogenous antagonist at NMDA receptors.
Bourguignon
J
J
Developmental Neuroendocrinology Unit, Department of Pediatrics, University of Liège, C.H.U. Sart Tilman, B-4000, Liège, Belgium. jean-pierre.bourguignon@chu.ulg.ac.be
Gérard
A
A
D000818:Animals; D010450:Endopeptidases / Q000494:pharmacology* / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000187:drug effects* / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D014701:Veratridine / Q000494:pharmacology
D016194:Receptors, N-Methyl-D-Aspartate; D007987:Gonadotropin-Releasing Hormone; D007334:Insulin-Like Growth Factor I; D014701:Veratridine; D010450:Endopeptidases; C095329:IGFBP-2 protease; C080473:insulin-like growth factor binding protein-3 protease