Intracellular mechanisms involved in copper-gonadotropin-releasing hormone (Cu-GnRH) complex-induced cAMP/PKA signaling in female rat anterior pituitary cells in vitro

Gajewska, Alina; Zielińska‐Górska, Marlena; Woliñska-Witort, Ewa; Siawrys, Gabriela; Baran, Marta; Kotarba, Grzegorz; Biernacka, Katarzyna

doi:10.1016/j.brainresbull.2015.11.002

Cited by 11 publications

(5 citation statements)

References 56 publications

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“…This would be further supported by Nterminal copper-binding not affecting the β-turn, with the overall structure remaining similar to the metal-free peptide, particularly in the C-terminal, receptor-binding region, Arg 8 -Gly 10 . The copper-complex will therefore bind to the GnRH receptor, but the activation profile will be different, as is observed experimentally (Kochman et al, 1992;Gajewska et al, 2016). A benefit of metal coordination to the N-terminal region is that the complex appears more resistant to degradation by peptidases, suggesting that enhanced LH/FSH release may be not only due to modified receptor binding properties, but also due to an increased half-life of the peptide (Herman et al, 2012).…”

Section: Copper Binding To Gnrh-i and Nkb Modifies The Structure And mentioning

confidence: 99%

“…A more recent study provided another perspective on how the copper-GnRH complex may enhance LH/FSH release by showing that it modified the intracellular signalling pathway compared to GnRH alone. The complex appears to activate the cyclic-AMP/protein kinase A (cAMP/PKA) pathway in preference to the inositol triphosphate/protein kinase C pathway triggered by the binding of metal-free GnRH to the GnRH receptor (Kochman et al, 2005;Gajewska et al, 2016). Activation of the cAMP/PKA pathway is thought to occur via binding of the complex with the GnRH receptor, however interaction of Cu-GnRH with the pituitary adenylate cyclase-activating polypeptide type 1 receptor was not discounted (Gajewska et al, 2016).…”

Section: The Role Of Copper In the Reproductive Axismentioning

confidence: 99%

“…The complex appears to activate the cyclic-AMP/protein kinase A (cAMP/PKA) pathway in preference to the inositol triphosphate/protein kinase C pathway triggered by the binding of metal-free GnRH to the GnRH receptor (Kochman et al, 2005;Gajewska et al, 2016). Activation of the cAMP/PKA pathway is thought to occur via binding of the complex with the GnRH receptor, however interaction of Cu-GnRH with the pituitary adenylate cyclase-activating polypeptide type 1 receptor was not discounted (Gajewska et al, 2016). Given that the Cu(II) coordinating amino acids of GnRH-I are pGlu 1 and His 2 and both these residues have been shown to be important for activating the receptor (vide infra) (Sealfon et al, 1997), it is plausible that modifying the structure of the N-terminal region could influence downstream intracellular signalling pathways.…”

Section: The Role Of Copper In the Reproductive Axismentioning

confidence: 99%

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Roles of copper in neurokinin B and gonadotropin-releasing hormone structure and function and the endocrinology of reproduction

Peacey

Elphick

Jones

2020

General and Comparative Endocrinology

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Copper is a metal ion present in all organisms, where it has well-known roles in association with proteins and enzymes essential for cellular processes. In the early decades of the twentieth century copper was shown to influence mammalian reproductive biology, and it was subsequently shown to exert effects primarily at the level of the pituitary gland and/or hypothalamic regions of the brain. Furthermore, it has been reported that copper can interact with key neuropeptides in the hypothalamic-pituitary-gonadal axis, notably gonadotropinreleasing hormone (GnRH) and neurokinin B. Interestingly, recent phylogenetic analysis of the sequences of GnRH-related peptides indicates that copper binding is an evolutionarily ancient property of this neuropeptide family, which has been variously retained, modified or lost in the different taxa. In this mini-review the metal-binding properties of neuropeptides in the vertebrate reproductive pathway are reviewed and the evolutionary and functional significance of copper binding by GnRH-related neuropeptides in vertebrates and invertebrates are discussed.

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Section: Copper Binding To Gnrh-i and Nkb Modifies The Structure And mentioning

confidence: 99%

Section: The Role Of Copper In the Reproductive Axismentioning

confidence: 99%

Section: The Role Of Copper In the Reproductive Axismentioning

confidence: 99%

See 1 more Smart Citation

Roles of copper in neurokinin B and gonadotropin-releasing hormone structure and function and the endocrinology of reproduction

Peacey

Elphick

Jones

2020

General and Comparative Endocrinology

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“…The mechanism for up‐regulation of gnrh2 and gnrh3 expression was not investigated, but GnRH is known to be regulated by kisspepsin, which in turn is regulated by neurokinin‐β (nkβ; Peacey, Elphick, et al, 2020 ). Both GnRH and nkb are known to bind Cu in vertebrates and echinoderms (Peacey, Elphick, et al, 2020 ; Peacey et al, 2020 ; Tran et al, 2019 ), with the Cu–GnRH complex having a higher affinity for GnRH receptors and/or triggering alternative signaling pathways that lead to enhanced release of FSH and LH compared with the unbound form (Gajewska et al, 2016 ). This suggests Cu, as an essential element, may have a regulatory role in GnRH activity even at normal, homeostatically controlled concentrations.…”

Section: Oxidative Stressmentioning

confidence: 99%

Adverse Outcome Pathways for Chronic Copper Toxicity to Fish and Amphibians

Brix

Boeck

Baken

et al. 2022

Enviro Toxic and Chemistry

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In the present review, we synthesize information on the mechanisms of chronic copper (Cu) toxicity using an adverse outcome pathway framework and identify three primary pathways for chronic Cu toxicity: disruption of sodium homeostasis, effects on bioenergetics, and oxidative stress. Unlike acute Cu toxicity, disruption of sodium homeostasis is not a driving mechanism of chronic toxicity, but compensatory responses in this pathway contribute to effects on organism bioenergetics. Effects on bioenergetics clearly contribute to chronic Cu toxicity with impacts at multiple lower levels of biological organization. However, quantitatively translating these impacts into effects on apical endpoints such as growth, amphibian metamorphosis, and reproduction remains elusive and requires further study. Copper-induced oxidative stress occurs in most tissues of aquatic vertebrates and is clearly a significant driver of chronic Cu toxicity. Although antioxidant responses and capacities differ among tissues, there is no clear indication that specific tissues are more sensitive than others to oxidative stress. Oxidative stress leads to increased apoptosis and cellular damage in multiple tissues, including some that contribute to bioenergetic effects. This also includes oxidative damage to tissues involved in neuroendocrine axes and this damage likely alters the normal function of these tissues. Importantly, Cu-induced changes in hormone concentrations and gene expression in endocrine-mediated pathways such as reproductive steroidogenesis and amphibian metamorphosis are likely the result of oxidative stress-induced tissue damage and not endocrine disruption. Overall, we conclude that oxidative stress is likely the primary driver of chronic Cu toxicity in aquatic vertebrates, with bioenergetic effects and compensatory response to disruption of sodium homeostasis contributing to some degree to observed effects on apical endpoints.

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“…This effect was predominantly due to effects early in the HPG axis which trigger the enhanced release of LH [9]. The effect of copper on LH release may occur in several different ways: The metal may directly release LH by modulating the activity of GnRH receptors on gonadotropic cells [10,11]; by amplifying the GnRH-I releasing activity of prostaglandin E2 [12]; by binding to GnRH-I and enhancing or modifying its receptor-binding activity [13][14][15]; and/or by binding to neurokinin B, a peptide that indirectly modulates GnRH-I release [16,17]. The ability of copper to modify the structure and function of GnRH-I and neurokinin B and influence early events in the HPG axis has recently been reviewed [18].…”

Section: Introductionmentioning

confidence: 99%

Copper(II) Binding by the Earliest Vertebrate Gonadotropin-Releasing Hormone, the Type II Isoform, Suggests an Ancient Role for the Metal

Peacey

Gutzinger

et al. 2020

IJMS

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In vertebrate reproductive biology copper can influence peptide and protein function both in the pituitary and in the gonads. In the pituitary, copper binds to the key reproductive peptides gonadotropin-releasing hormone I (GnRH-I) and neurokinin B, to modify their structure and function, and in the male gonads, copper plays a role in testosterone production, sperm morphology and, thus, fertility. In addition to GnRH-I, most vertebrates express a second isoform, GnRH-II. GnRH-II can promote testosterone release in some species and has other non-reproductive roles. The primary sequence of GnRH-II has remained largely invariant over millennia, and it is considered the ancestral GnRH peptide in vertebrates. In this work, we use a range of spectroscopic techniques to show that, like GnRH-I, GnRH-II can bind copper. Phylogenetic analysis shows that the proposed copper-binding ligands are retained in GnRH-II peptides from all vertebrates, suggesting that copper-binding is an ancient feature of GnRH peptides.

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Intracellular mechanisms involved in copper-gonadotropin-releasing hormone (Cu-GnRH) complex-induced cAMP/PKA signaling in female rat anterior pituitary cells in vitro

Cited by 11 publications

References 56 publications

Roles of copper in neurokinin B and gonadotropin-releasing hormone structure and function and the endocrinology of reproduction

Roles of copper in neurokinin B and gonadotropin-releasing hormone structure and function and the endocrinology of reproduction

Adverse Outcome Pathways for Chronic Copper Toxicity to Fish and Amphibians

Copper(II) Binding by the Earliest Vertebrate Gonadotropin-Releasing Hormone, the Type II Isoform, Suggests an Ancient Role for the Metal

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