A ligand-specific action of chelated copper on hypothalamic neurons: stimulation of the release of luteinizing hormone-releasing hormone from median eminence explants.

We have previously shown that chelated copper stimulates the release of luteinizing hormone-releasing hormone (LHRH) from isolated hypothalamic granules. In this study, we wished to ascertain if chelated copper acts on hypothalamic neurons to stimulate LHRH release and, if so, what is the ligand specificity of this interaction. An in vitro system of explants of the median eminence area (MEA) was established and characterized. MEA explants were exposed for 15 min to 50 microM copper, and then they were incubated for 75 min in copper-free medium. Copper led to a transient increase in the rate of LHRH release; the maximal rate was attained 15 min after transfer of the MEA to copper-free medium. In addition, we found that copper complexed to histidine (Cu-His), but not ionic copper, stimulated LHRH release, the magnitude of which was dependent on the dose of Cu-His. The chelator specificity for Cu complex action was such that Cu-His stimulated LHRH release 4.9-fold and Cu-Cys stimulated release 2.5-fold, whereas neither Cu-Thr, Cu-Gly-His-Lys, Cu-bovine serum albumin, nor ceruloplasmin stimulated LHRH release. Based on these results and those of others indicating that the concentration of copper in hypothalamic axonal terminals is 1-2 orders of magnitude greater than plasma, we propose that copper released in the vicinity of the LHRH neurons interacts with specific sites on the LHRH axonal terminals, which leads to release of the peptide.