A Possible Role for Copper‐Mediated Oxidation of Thiols in the Regulation of the Release of Luteinizing Hormone Releasing Hormone from Isolated Hypothalamic Granules

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Abstract
A role for copper in the release of luteinizing hormone releasing hormone (LHRH) from hypothalamic neurons has been previously proposed. To elucidate further the mechanism of action of copper, we addressed two questions: (a) what is the active form of copper that interacts with the LHRH granule (ionic or chelated)? and (b) is copper‐stimulated LHRH release a result of an interaction of copper with thiol groups and, if so, does it require oxygen? Granules were isolated from hypothalami of adult male rats and were then incubated at 37°C for 3–5 min in a buffered medium. When granules were incubated with various copper complexes, CuATP stimulated LHRH release by 45 ± 4% (mean ± SE), copper tartrate by 44 ± 4%, CuBSA by 27 ± 7%, and copper histidine by 16 ± 6%. Neither CuEDTA nor CuCl2 stimulated LHRH release. CuATP‐stimulated LHRH release from granules incubated under N2 was 50% of that incubated under air. Furthermore, the CuATP‐stimulated release of LHRH was completely inhibited by dithiothreitol or glutathione (10−3M each), partially (40–50%) by iodoacetate or 5,5‐dithiobis‐(2‐nitrobenzoic acid), and not at all by oxidized dithiothreitol. Thus, chelated copper, rather than ionic copper, is the active form of the metal, and the action of copper involves an oxidation reaction and granule thiol groups. The precise mechanism of action of copper, however, has yet to be elucidated. We propose that copper may affect LHRH release as follows: copper, bound to an intracellular chelator (protein, peptide, or amino acid), oxidizes thiols of the LHRH granule, leading to a change in granule‐membrane permeability and hence to LHRH release.