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This Article Full Text Full Text (PDF) All Versions of this Article: 578/3/765    most recent jphysiol.2006.123083v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, B. Articles by Dees, W. L. Search for Related Content PubMed PubMed Citation Articles by Lee, B. Articles by Dees, W. L. Related Collections Neuroscience

¹ Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A & M University, College Station, TX 77843-4458, USA

We have shown recently that Mn²⁺ stimulates gonadotropin secretion via an action at the hypothalamic level, and a diet supplemented with a low dose of the element is capable of advancing the time of female puberty. In this study, we used an in vitro approach to investigate the mechanism by which Mn²⁺ induces luteinizing hormone-releasing hormone (LHRH) secretion from prepubertal female rats. The medial basal hypothalamus from 30-day-old rats was incubated in Locke solution for 30 min to assess basal LHRH secretion, then incubated with buffer alone or buffer plus either a nitric oxide synthase (NOS) inhibitor (N-monomethyl-L-arginine (NMMA); 300 or 500 µM) or a soluble guanylyl cyclase (sGC) inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ); 100 or 250 µM) for another 30 min. Finally, the incubation continued for a further 30 min, but in the presence of MnCl₂ (50 or 250 µM) to assess the effect of the blockers on stimulated LHRH secretion. Both 50 and 250 µM MnCl₂ stimulated LHRH release (P < 0.05 and P < 0.01, respectively). The addition of 300–500 µM NMMA to the medium did not block Mn²⁺-stimulated release of LHRH, even with the higher dose of MnCl₂. Furthermore, while 50, 100 and 250 µM MnCl₂ all significantly induced LHRH release, the two lowest doses did not stimulate total nitrite released from the same tissue, an effect only observed with the highest dose. Taken together, these data suggest that Mn²⁺ is not an effective stimulator of NO. Conversely, inhibiting sGC with ODQ blocked the Mn²⁺-stimulated secretion of LHRH in a dose-dependent manner, indicating that GC is the site of action of Mn²⁺. Additionally, we showed that Mn²⁺ stimulated cGMP and LHRH from the same tissues, and that downstream blocking of protein kinase G formation with KT5823 (10 µM) inhibited Mn²⁺-induced LHRH release. These data demonstrate that the principal action of Mn²⁺ within the hypothalamus is to activate sGC directly and/or as a cofactor with available NO, hence generating cGMP and resulting in prepubertal LHRH release.

(Received 18 October 2006; accepted after revision 10 November 2006; first published online 16 November 2006)
Corresponding author W. L. Dees: College of Veterinary Medicine, Texas A & M University, College Station, TX 77843-4458, USA. Email: ldees{at}cvm.tamu.edu

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