Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Sep 15;89(18):8462–8466. doi: 10.1073/pnas.89.18.8462

Calcium signaling and episodic secretion of gonadotropin-releasing hormone in hypothalamic neurons.

L Z Krsmanović 1, S S Stojilković 1, F Merelli 1, S M Dufour 1, M A Virmani 1, K J Catt 1
PMCID: PMC49940  PMID: 1326758

Abstract

Gonadotropin-releasing hormone (GnRH) is released episodically into the pituitary portal vessels and from hypothalamic tissue of male and female rats in vitro. Perifused primary cultures of rat hypothalamic neurons, as well as the GT1-1 GnRH neuronal cell line, spontaneously exhibited episodic GnRH secretion of comparable frequency to that observed with perifused hypothalami. Such pulsatile GnRH release from GT1 cells indicates that GnRH neurons generate rhythmic secretory activity in the absence of input from other cell types. In primary hypothalamic cultures, the frequency of GnRH pulses increased with the duration of culture. The spontaneous pulsatility in GnRH release was abolished in Ca(2+)-deficient medium and was markedly attenuated in the presence of nifedipine, an antagonist of voltage-sensitive Ca2+ channels. The basal intracellular Ca2+ level of perifused GT1-1 cells cultured on coverslips was also dose-dependently reduced by nifedipine. Conversely, depolarization with high K+ increased intracellular Ca2+ and GnRH release in an extracellular Ca(2+)-dependent and nifedipine-sensitive manner. The dihydropyridine Ca2+ channel agonist Bay K 8644 increased basal and K(+)-induced elevations of intracellular Ca2+ concentration and GnRH secretion. These findings demonstrate that pulsatile neuropeptide secretion is an intrinsic property of GnRH neuronal networks and is dependent on voltage-sensitive Ca2+ influx for its maintenance.

Full text

PDF
8462

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adler B. A., Crowley W. R. Evidence for gamma-aminobutyric acid modulation of ovarian hormonal effects on luteinizing hormone secretion and hypothalamic catecholamine activity in the female rat. Endocrinology. 1986 Jan;118(1):91–97. doi: 10.1210/endo-118-1-91. [DOI] [PubMed] [Google Scholar]
  2. Bigdeli H., Snyder P. J. Gonadotropin releasing hormone release from the rat hypothalamus: dependence on membrane depolarization and calcium influx. Endocrinology. 1978 Jul;103(1):281–286. doi: 10.1210/endo-103-1-281. [DOI] [PubMed] [Google Scholar]
  3. Bourguignon J. P., Franchimont P. Puberty-related increase in episodic LHRH release from rat hypothalamus in vitro. Endocrinology. 1984 May;114(5):1941–1943. doi: 10.1210/endo-114-5-1941. [DOI] [PubMed] [Google Scholar]
  4. Bourguignon J. P., Gérard A., Franchimont P. Maturation of the hypothalamic control of pulsatile gonadotropin-releasing hormone secretion at onset of puberty: II. Reduced potency of an inhibitory autofeedback. Endocrinology. 1990 Dec;127(6):2884–2890. doi: 10.1210/endo-127-6-2884. [DOI] [PubMed] [Google Scholar]
  5. Chieffi G., Pierantoni R., Fasano S. Immunoreactive GnRH in hypothalamic and extrahypothalamic areas. Int Rev Cytol. 1991;127:1–55. doi: 10.1016/s0074-7696(08)60691-9. [DOI] [PubMed] [Google Scholar]
  6. Clarke I. J., Cummins J. T. The temporal relationship between gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) secretion in ovariectomized ewes. Endocrinology. 1982 Nov;111(5):1737–1739. doi: 10.1210/endo-111-5-1737. [DOI] [PubMed] [Google Scholar]
  7. Drouva S. V., Epelbaum J., Hery M., Tapia-Arancibia L., Laplante E., Kordon C. Ionic channels involved in the LHRH and SRIF release from rat mediobasal hypothalamus. Neuroendocrinology. 1981 Mar;32(3):155–162. doi: 10.1159/000123149. [DOI] [PubMed] [Google Scholar]
  8. Drouva S. V., Laplante E., Kordon C. Effects of ovarian steroids on in vitro release of LHRH from mediobasal hypothalamus. Neuroendocrinology. 1983 Nov;37(5):336–341. doi: 10.1159/000123572. [DOI] [PubMed] [Google Scholar]
  9. Franco B., Guioli S., Pragliola A., Incerti B., Bardoni B., Tonlorenzi R., Carrozzo R., Maestrini E., Pieretti M., Taillon-Miller P. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature. 1991 Oct 10;353(6344):529–536. doi: 10.1038/353529a0. [DOI] [PubMed] [Google Scholar]
  10. Gearing M., Terasawa E. The alpha-1-adrenergic neuronal system is involved in the pulsatile release of luteinizing hormone-releasing hormone in the ovariectomized female rhesus monkey. Neuroendocrinology. 1991 Apr;53(4):373–381. doi: 10.1159/000125744. [DOI] [PubMed] [Google Scholar]
  11. Kalra S. P., Kalra P. S. Do testosterone and estradiol-17 beta enforce inhibition or stimulation of luteinizing hormone-releasing hormone secretion? Biol Reprod. 1989 Oct;41(4):559–570. doi: 10.1095/biolreprod41.4.559. [DOI] [PubMed] [Google Scholar]
  12. Karsch F. J., Cummins J. T., Thomas G. B., Clarke I. J. Steroid feedback inhibition of pulsatile secretion of gonadotropin-releasing hormone in the ewe. Biol Reprod. 1987 Jun;36(5):1207–1218. doi: 10.1095/biolreprod36.5.1207. [DOI] [PubMed] [Google Scholar]
  13. King J. C., Anthony E. L. LHRH neurons and their projections in humans and other mammals: species comparisons. Peptides. 1984;5 (Suppl 1):195–207. doi: 10.1016/0196-9781(84)90277-8. [DOI] [PubMed] [Google Scholar]
  14. Knobil E. Patterns of hypophysiotropic signals and gonadotropin secretion in the rhesus monkey. Biol Reprod. 1981 Feb;24(1):44–49. doi: 10.1095/biolreprod24.1.44. [DOI] [PubMed] [Google Scholar]
  15. Knobil E. The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res. 1980;36:53–88. doi: 10.1016/b978-0-12-571136-4.50008-5. [DOI] [PubMed] [Google Scholar]
  16. Krsmanović L. Z., Stojilković S. S., Balla T., al-Damluji S., Weiner R. I., Catt K. J. Receptors and neurosecretory actions of endothelin in hypothalamic neurons. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11124–11128. doi: 10.1073/pnas.88.24.11124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Leranth C., Segura L. M., Palkovits M., MacLusky N. J., Shanabrough M., Naftolin F. The LH-RH-containing neuronal network in the preoptic area of the rat: demonstration of LH-RH-containing nerve terminals in synaptic contact with LH-RH neurons. Brain Res. 1985 Oct 21;345(2):332–336. doi: 10.1016/0006-8993(85)91011-x. [DOI] [PubMed] [Google Scholar]
  18. Liposits Z., Merchenthaler I., Wetsel W. C., Reid J. J., Mellon P. L., Weiner R. I., Negro-Vilar A. Morphological characterization of immortalized hypothalamic neurons synthesizing luteinizing hormone-releasing hormone. Endocrinology. 1991 Sep;129(3):1575–1583. doi: 10.1210/endo-129-3-1575. [DOI] [PubMed] [Google Scholar]
  19. Marshall J. C., Dalkin A. C., Haisenleder D. J., Paul S. J., Ortolano G. A., Kelch R. P. Gonadotropin-releasing hormone pulses: regulators of gonadotropin synthesis and ovulatory cycles. Recent Prog Horm Res. 1991;47:155–189. doi: 10.1016/b978-0-12-571147-0.50009-3. [DOI] [PubMed] [Google Scholar]
  20. Martínez de la Escalera G., Choi A. L., Weiner R. I. Generation and synchronization of gonadotropin-releasing hormone (GnRH) pulses: intrinsic properties of the GT1-1 GnRH neuronal cell line. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1852–1855. doi: 10.1073/pnas.89.5.1852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mellon P. L., Windle J. J., Goldsmith P. C., Padula C. A., Roberts J. L., Weiner R. I. Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis. Neuron. 1990 Jul;5(1):1–10. doi: 10.1016/0896-6273(90)90028-e. [DOI] [PubMed] [Google Scholar]
  22. Merchenthaler I., Görcs T., Sétáló G., Petrusz P., Flerkó B. Gonadotropin-releasing hormone (GnRH) neurons and pathways in the rat brain. Cell Tissue Res. 1984;237(1):15–29. doi: 10.1007/BF00229195. [DOI] [PubMed] [Google Scholar]
  23. Moenter S. M., Brand R. M., Midgley A. R., Karsch F. J. Dynamics of gonadotropin-releasing hormone release during a pulse. Endocrinology. 1992 Jan;130(1):503–510. doi: 10.1210/endo.130.1.1727719. [DOI] [PubMed] [Google Scholar]
  24. O'Byrne K. T., Thalabard J. C., Grosser P. M., Wilson R. C., Williams C. L., Chen M. D., Ladendorf D., Hotchkiss J., Knobil E. Radiotelemetric monitoring of hypothalamic gonadotropin-releasing hormone pulse generator activity throughout the menstrual cycle of the rhesus monkey. Endocrinology. 1991 Sep;129(3):1207–1214. doi: 10.1210/endo-129-3-1207. [DOI] [PubMed] [Google Scholar]
  25. Ramirez V. D., Gallardo E., Hartter D. Factors altering the secretion of LHRH from superfused fragments of rat hypothalamus. J Endocrinol Invest. 1980 Jan-Mar;3(1):29–37. doi: 10.1007/BF03348214. [DOI] [PubMed] [Google Scholar]
  26. Rasmussen D. D., Gambacciani M., Swartz W., Tueros V. S., Yen S. S. Pulsatile gonadotropin-releasing hormone release from the human mediobasal hypothalamus in vitro: opiate receptor-mediated suppression. Neuroendocrinology. 1989 Feb;49(2):150–156. doi: 10.1159/000125107. [DOI] [PubMed] [Google Scholar]
  27. Schwanzel-Fukuda M., Pfaff D. W. Origin of luteinizing hormone-releasing hormone neurons. Nature. 1989 Mar 9;338(6211):161–164. doi: 10.1038/338161a0. [DOI] [PubMed] [Google Scholar]
  28. Smith M. A., Vale W. W. Desensitization to gonadotropin-releasing hormone observed in superfused pituitary cells on Cytodex beads. Endocrinology. 1981 Mar;108(3):752–759. doi: 10.1210/endo-108-3-752. [DOI] [PubMed] [Google Scholar]
  29. Stojilković S. S., Iida T., Virmani M. A., Izumi S., Rojas E., Catt K. J. Dependence of hormone secretion on activation-inactivation kinetics of voltage-sensitive Ca2+ channels in pituitary gonadotrophs. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8855–8859. doi: 10.1073/pnas.87.22.8855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Stojilković S. S., Izumi S., Catt K. J. Participation of voltage-sensitive calcium channels in pituitary hormone release. J Biol Chem. 1988 Sep 15;263(26):13054–13061. [PubMed] [Google Scholar]
  31. Veldhuis J. D., Rogol A. D., Samojlik E., Ertel N. H. Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man. J Clin Invest. 1984 Jul;74(1):47–55. doi: 10.1172/JCI111417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Veldhuis J. D. The hypothalamic pulse generator: the reproductive core. Clin Obstet Gynecol. 1990 Sep;33(3):538–550. doi: 10.1097/00003081-199009000-00021. [DOI] [PubMed] [Google Scholar]
  33. Wetsel W. C., Valença M. M., Merchenthaler I., Liposits Z., López F. J., Weiner R. I., Mellon P. L., Negro-Vilar A. Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone-secreting neurons. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4149–4153. doi: 10.1073/pnas.89.9.4149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Williams C. L., Thalabard J. C., O'Byrne K. T., Grosser P. M., Nishihara M., Hotchkiss J., Knobil E. Duration of phasic electrical activity of the hypothalamic gonadotropin-releasing hormone pulse generator and dynamics of luteinizing hormone pulses in the rhesus monkey. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8580–8582. doi: 10.1073/pnas.87.21.8580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Witkin J. W., Ferin M., Popilskis S. J., Silverman A. J. Effects of gonadal steroids on the ultrastructure of GnRH neurons in the rhesus monkey: synaptic input and glial apposition. Endocrinology. 1991 Aug;129(2):1083–1092. doi: 10.1210/endo-129-2-1083. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES