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

Abstract

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.

Adverse Outcome Pathways for Chronic Copper Toxicity to Fish and Amphibians

“…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.…”

Correction: Peacey, L., et al. Copper(II) Binding by the Earliest Vertebrate Gonadotropin-Releasing Hormone, the Type II Isoform, Suggests an Ancient Role for the Metal. Int. J. Mol. Sci. 2020, 21, 7900

“…The authors wish to make the following correction to this paper [ 1 ]. Due to an incorrect phylogenetic tree, Figure 5 should be replaced with the following figure ( Figure 1 ).…”