Effects of Castration and Maturational Age of Male Rats on the Process of Copper-Stimulated Release of Luteinizing Hormone Releasing Hormone from Median Eminence Explants: Evidence that Androgens Increase the Affinity of the Copper-Interactive Sites for Copper

Colombani-Vidal, Miriam; Barnea, Ayalla

doi:10.1159/000124219

Cited by 11 publications

(5 citation statements)

References 30 publications

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“…7A,B ). Conspicuously, the strongest pathway finding involves steroid biosynthesis and metabolism, processes previously found to be significantly dependent on both mitochondrial function(39) and Cu(I) homeostasis(40-42).…”

Section: Resultsmentioning

confidence: 94%

Glial swip-10expression controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

Rodriguez,

Kalia,

Gibson

et al. 2023

Preprint

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Cuprous copper (Cu(I)) is an essential cofactor for enzymes supporting many cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly dependent on these pathways, with multiple neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, associated with their dysfunction. Key features of Cu(I) contributions to neuronal healthin vivoremain to be defined, owing largely to the complex processes involved in Cu(I) production, intracellular transport, and systemic redistribution. Here, we provide genetic and pharmacological evidence thatswip-10is a critical determinant of systemic Cu(I) levels inC. elegans, with deletion leading to systemic deficits in mitochondrial respiration, production of oxidative stress, and neurodegeneration. These phenotypes can be reproduced in wild-type worms by Cu(I)-specific chelation and offset inswip-10mutants by growth on the Cu(I) enhancing molecule elesclomol, as well as by glial expression of wildtypeswip-10.MBLAC1, the most closely related mammalian ortholog toswip-10, encodes for a pre-mRNA processing enzyme for H3 histone, a protein whose actions surprisingly include an enzymatic capacity to produce Cu(I) via the reduction of Cu(II). Moreover, genome-wide association studies and post-mortem molecular studies implicate reductions ofMBLAC1expression in risk for AD with cardiovascular disease comorbidity. Consistent with these studies, we demonstrate that the deposition of β-amyloid plaques, an AD pathological hallmark, in worms engineered to express human Aβ1-42,is greatly exaggerated by mutation ofswip-10. Together, these studies identify a novel glial-expressed, and pathway for Cu(I) production that may be targeted for the treatment of AD and other neurodegenerative diseases.Significance StatementDevastating neurodegenerative diseases such as Alzheimer’s disease, and Parkinson’s disease are associated with disruptions in copper (Cu) homeostasis. Alterations in Cu(I) give rise to increased oxidative stress burden, mitochondrial and metabolic dysfunction, and can accelerate production and/or potentiate toxicity of disease-associated protein aggregates. Here, using the model systemCaenorhabditis elegans, we establish a role for the geneswip-10in systemic Cu(I) homeostasis. Perturbation of this pathway in worms recapitulates biochemical, histological, and pathological features seen in human neurodegenerative disease. We reveal that these changes can be suppressed pharmacologically and arise whenswip-10expression is eliminated from glial cells. Our work implicatesswip-10and orthologs as key players in Cu(I) homeostasis that may be exploitable to treat multiple neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 94%

Glial swip-10expression controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

Rodriguez,

Kalia,

Gibson

et al. 2023

Preprint

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“…First, we will address the time course of CuHis-stimulated release of LHRH. We [9] have previously shown that when MEA is incubated with CuHis for 15 min, there is a lag period of 5 min before an increase in LHRH release is demonstrable and, thereafter, the release increases in an exponential manner for a period of about 25 min. An exponential re lease of LHRH after transfer of the MEA to CuHis-free me dium is consistent with compound exocytosis.…”

Section: Discussionmentioning

confidence: 92%

“…Consistent with this hypothesis are the findings of Tsou et al [28] that systemic administration of cupric acetate results in elevated levels of LHRH in the hy pophysial portal blood and our[2| finding that copper stim ulates LHRH release from explants of the median emi nence area (MEA), i.e., the LHRH axonal terminals. This in vitro LHRH release process has the following characteris tics: chelated copper is the active form of the metal [2]; a limited number of copper interactive sites are involved [9] and metabolic energy is required [8]. Based on the kinetic parameters of the process of copper-stimulated release, we proposed that newly taken-up copper interacts with the I HRH granules that are in close proximity to the plasma membrane of the LHRH neuronal terminal.…”

mentioning

confidence: 99%

Copper Stimulation of LHRH Release from Median Eminence Explants

Colombani-Vidal¹,

Barnea²

1986

Neuroendocrinology

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We have previously shown that chelated copper stimulates LHRH release from explants of the median eminence area (MEA). Characteristics of this release process are: ligand and metal specificity, the involvement of a limited number of copper interactive sites, and a lack of dependence on extracellular calcium. Since chloride transport is essential for exocytosis of peptides and biogenic amines, we wished to ascertain if chloride transport is essential for the process of CuHis-stimulated release of LHRH. MEA explants were incubated for 15 min with 100 µM CuHis (phase I) and then for 15 min in copper-free medium (phase II) and LHRH released into the medium was evaluated by RIA. In the presence of 136 mM Cl, CuHis stimulated the release of LHRH from a basal level of 5±0.4pg/15 min per MEA to 17 + 0.9 pg during phase I and to 30 ± 1.2 pg during phase II. In the absence of Cl∼, the CuHis-stimulated release of LHRH during phases I and II was inhibited by 80 and 90%, respectively. In the presence of 136 mMCL and the anion transport inhibitor SITS (4-acetamido-4’-isothiocyanostilbene-2, 2’-disulfonic acid) the stimulated release was completely inhibited in both phases. When the selectivity of this release process for monovalent anions was tested, the effectiveness of the anions in supporting CuHis-stimulated LHRH release was in this decreasing order: Cl^– > Br^– > SCN^– = acetate > I^– = isethionate. In addition, we noted that CuHis-stimulated release was a saturable function of [CL]; the saturating [Cl^–] for phase I was about 40 mM and the shape of the curve was hyperbolic; the saturating [Cl^–] for phase II was about 100 mM and the curve was sigmoid. These results indicate that the process of CuHis-stimulated release of LHRH (1) is dependent on chloride transport, (2) exhibits a selectivity for monovalent anions and (3) involves a limited number of CL transport sites. The hyperbolic and sigmoid shapes of the [CL] curves are consistent with a single population of Cl^– transport sites involved in LHRH release during the exposure to CuHis and with multiple populations after the exposure to CuHis. We propose that the process of CuHis-stimulated release of LHRHoperates by compound exocytosis in which an influx of chloride leads to LHRH release by chemiosmotic lysis.

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“…We [3,10] have previously hypothesized that uptake of CuHis by the LHRH axonal terminal is the initial step in the cascade of events leading to LHRH release. It has been shown that uptake of several small molecular weight sub stances, e.g., amino acids, glucose or ascorbate, is achieved by co-transport with Na*, the driving force of which is the electrochemical Na* gradient.…”

Section: Discussionmentioning

confidence: 99%

“…In a series of studies, we have recently demonstrated that cop per stimulates the release of LHRH from explants of the median eminence area (MEA) and that one site of copper action is the LHRH secretory granule itself [2,3,5]. The time course of copper action and the fact that chelated cop per is the active form of the metal led us to postulate that uptake of extracellular copper by the LHRH neuronal teminals is involved in this release process [3,10], It is well documented that tissues derive their copper from blood. The findings that the levels of copper in hypo thalamic tissue [13,27] and in isolated axonal terminals (synaptosomes) [33] are at least two orders of magnitude greater than in blood are indicative that an uptake mecha nism for copper is operative in the hypothalamus.…”

mentioning

confidence: 99%

Copper Stimulation of LHRH Release from Median Eminence Explants

Colombani-Vidal¹,

Barnea²

1986

Neuroendocrinology

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Copper, complexed to histidine (CuHis), stimulates LHRH release from explants of the median eminence area (MEA). To gain further understanding of the mechanism of copper action, in this study, we assessed the Na⁺ and energy requirements for CuHis stimulation of LHRH release. MEA explants, obtained from adult male rats, were incubated at 37 °C for 15 min with 100 µM CuHis and then for 45 min in CuHis-free medium (Krebs-Ringer-phosphate buffer, pH 7.4). LHRH released into the medium was evaluated by RIA. When the incubation buffer contained 143 mM Na⁺, CuHis stimulated the release of LHRH from a basal level of 17.2 ± 1.26 (mean ± SEM, n = 7) to 74.5 ±6.2 pg/60 min per MEA. When [Na⁺] was reduced to 16 mM Na⁺ (by substituting with Li⁺), CuHis-stimulated LHRH release was inhibited by 80% (p< 0.001); indicating a requirement for Na⁺. In addition, we found that CuHis-stimulated LHRH release was a saturable function of Na⁺ concentration; saturation achieved with about 100 mM Na⁺. To assess the requirement for Na⁺ transport, we evaluated the effect of 1 mM ouabain, 10 µMtetrodotoxin (TTX), or 100 µM amiloride on CuHis stimulation of LHRH release. Ouabain inhibited CuHis stimulation of LHRH release by 80%, whereas TTX and amiloride were ineffective. In addition, we observed that CuHis did not stimulate LHRH release when incubation was carried out at 4 °C or at 37 °C in the presence of 5 mM KCN. In summary, these results indicate that the process of CuHis-stimulated release of LHRH from the median eminence has a requirement for extracellular Na⁺, for thermic and metabolic energy, for the activity of the enzyme Na⁺/K⁺ ATPase, and for Na⁺ transport by a limited number of sites. These requirements are supportive of the proposition that CuHis is taken up by the LHRH axonal terminal by co-transport with Na⁺, the driving force of which is the Na⁺ electrochemical gradient generated by NaVK⁺ ATPase.

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Effects of Castration and Maturational Age of Male Rats on the Process of Copper-Stimulated Release of Luteinizing Hormone Releasing Hormone from Median Eminence Explants: Evidence that Androgens Increase the Affinity of the Copper-Interactive Sites for Copper

Cited by 11 publications

References 30 publications

Glial swip-10expression controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

Glial swip-10expression controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

Copper Stimulation of LHRH Release from Median Eminence Explants

Copper Stimulation of LHRH Release from Median Eminence Explants

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