[en] The secretion of GnRH can be stimulated by glutamate (GLU) and GLU agonists, whereas GLU receptor antagonists inhibit GnRH. Using 6-diazo-5-oxo-L-norleucine (DON), an inhibitor of glutaminase, we aimed to study the involvement of endogenous GLU in GnRH secretion through the effects of impaired GLU biosynthesis from its precursor glutamine (GLN). GnRH secretion by hypothalamic explants of male rats, aged 15 and 50 days, was compared, because the frequency of spontaneous GnRH secretory pulses showed a 2-fold increase between those two ages. Using explants of 50-day-old rats, GLN elicited GnRH secretion in a similar dose-related manner as GLU. DON prevented GLN-evoked secretion of GnRH, whereas the effect of GLU was not altered. DON also markedly inhibited spontaneous pulsatile secretion of GnRH and the secretory response to veratridine, a Na+ channel opener. The inhibitory effect of DON on veratridine-evoked secretion of GnRH was directly related to the duration of exposure to DON and the frequency of GnRH secretory episodes. Using explants of 15-day-old rats, GLN could elicit GnRH release, although this response was lower than GLU-evoked secretion of GnRH. The DON concentrations required for inhibition of veratridine-evoked secretion of GnRH were lower at 15 days than at 50 days. These data indicate that 1) GLU biosynthesis from GLN is a prerequisite to the physiological mechanism of pulsatile GnRH secretion; and 2) inhibition of veratridine- or GLN-induced secretion of GnRH requires higher DON concentrations after the onset of puberty than before. This suggests that glutaminase, the enzyme controlling GLU biosynthesis from GLN, shows increased activity after the onset of puberty when the frequency of pulsatile GnRH secretion is increased as well.
Disciplines :
Pediatrics
Author, co-author :
Bourguignon, Jean-Pierre ; Université de Liège - ULiège > Département des sciences cliniques > Pédiatrie
Gerard, Arlette ; Centre Hospitalier Universitaire de Liège - CHU > Pédiatrie
Alvarez Gonzalez, Maria-Luz ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Purnelle, Gentiane; Centre Hospitalier Universitaire de Liège - CHU > Pédiatrie
Franchimont, P.
Language :
English
Title :
Endogenous Glutamate Involvement in Pulsatile Secretion of Gonadotropin-Releasing Hormone: Evidence from Effect of Glutamine and Developmental Changes
Urbanski HF, Ojeda SR 1987 Activation of luteinizing hormonereleasing hormone release advances the onset of female puberty. Neuroendocrinology 46:273-276
Plant TM, Gay VL, Marshall GR, Arslan M 1989 Puberty in monkeys is triggered by chemical stimulation. Proc Natl Acad Sci USA86:2506-2510
Bourguignon JP, Gerard A, Franchimont P 1989 Direct activation of GnRH secretion through different receptors to neuroexcitatory amino acids. Neuroendocrinology 49:402-408
Bourguignon JP, Gerard A, Mathieu J, Simons J, Franchimont P 1989 Pulsatile release of gonadotropin releasing hormone from hypothalamic explants is restrained by blockade of N-methyl-D, l-as-partate receptors. Endocrinology 125:1090-1096
Mahachoklertwattana P, Sanchez J, Kaplan SL, Grumbach MM1994 N-Methyl-D-aspartate (NMDA) receptors mediate the release of gonadotropin-releasing hormone (GnRH) by NMDA in a hypothalamic GnRH neuronal cell line (GT1-1). Endocrinology 134:1023-1030
Goldsmith PC, Thind KK, Perera AD, Plant TM 1994 Glutamate-immunoreactive neurons and their Gonadotropin-releasing hormone-neuronal interactions in the monkey hypothalamus. Endocrinology 134:858-868
Nicklas WJ 1983 Relative contributions of neurons and glia to metabolism of glutamate and GABA. In: Hertz L; Kvamme E, McGeer ED, Schousboe A (eds) Glutamine, Glutamate, and GABA in the Central Nervous System. Liss, New York, pp 219-231
Bourguignon JP, Franchimont P 1984 Puberty-related increase in episodic LHRH release from rat hypothalamus in vitro. Endocrinology 114:1941-1943
Bourguignon JP, Gerard A, Mathieu J, Mathieu A Franchimont P 1990 Maturation of the hypothalamic control of pulsatile gonadotropin-releasing hormone secretion at onset of puberty: I. Increased activation of N-methyl-D-aspartate receptors. Endocrinology 127: 873-881
Bourguignon JP, Gerard A, Alvarez Gonzalez ML, Franchimont P 1992 The neuroendocrine mechanism of onset of puberty: sequential reduction in activity of inhibitory and facilitatory N-methyl-D-aspartate receptors. J Clin Invest 90:1736-1744
Merriam GR, Wachter KW 1982 Algorithms for the study of episodic hormone secretion. Am J Physiol 243:E310-E318
Berl S, Clarke DD 1969 Compartmentation of amino acid metabolism. In: Lajtha A (ed) Handbook of Neurochemistry. Plenum Press, New York, vol 2:447-472
Cooper AJL, Vergara F, Duffy TE 1983 Cerebral glutamine synthetase. In: Hertz L, Kvamme E, McGeer E, Schousboe A (eds) Glutamine, Glutamate, and GABA in the Central Nervous System. Liss, New York, pp 77-93
Hertz L, Yu ACH, Potter RL, et al 1983 Metabolic fluxes from glutamate and towards glutamate in neurons and astrocytes in primary cultures. In: Hertz L, Kvamme E, McGeer E, Schousboe A (eds) Glutamine, Glutamate, and GABA in the Central Nervous System. Liss, New York, pp 327-342
Kvamme E 1983 Glutaminase (PAG). In: Hertz L, Kvamme E, McGeer E, Schousboe A (eds) Glutamine, Glutamate and GABA in the Central Nervous System. Liss, New York, pp 51-67
Albrecht J 1989 L-Glutamate stimulates the efflux of newly taken up glutamine from astroglia but not from synaptosomes of the rat. Neuropharmacology 28:885-887
Pinkus LM 1977 Glutamine binding site. In: Jakoby WB, Wilchek M (eds) Methods in Enzymology. Academic Press, London vol 46:414-427
Bradford HF, Ward HK, Foley P 1989 Glutaminase inhibition and the release of neurotransmitter glutamate from synaptosomes. Brain Res 476:29-34
Hartman SC 1968 Glutaminase of Escherichia coli. I. Purification and general catalytic properties. J Biol Chem 243:853-863
Bourguignon JP, Gerard A, Alvarez Gonzalez ML, Fawe L, Franchimont P 1992 Gonadal-independent developmental changes in activation of N-methyl-D-aspartate receptors involved in gonadotropin-releasing hormone secretion. Neuroendocrinology 55: 634-641
Mennerick S, Zorumski CF 1994 Glial contributions to excitatory neurotransmission in cultured hippocampal cells. Nature 368:59-62
Mitsushima D, Hei DL, Terasawa E 1994 Gamma-aminobutyric acid is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before onset of puberty. Proc Natl Acad Sci USA 91:395-399