# Evolution of neurohormone function revealed by actions of kisspeptin-type peptides in an echinoderm

## TL;DR

This paper explores how kisspeptin-type peptides in starfish regulate various physiological processes, revealing their evolutionary origins and diverse functions.

## Contribution

The study identifies two kisspeptin precursor proteins in starfish and shows their neuropeptides have opposing effects on muscle activity and behavior.

## Key findings

- Kisspeptin-type neuropeptides in starfish have myoinhibitory and myoexcitatory effects on gonads and stomach.
- ArKP2.2 acts as a ligand for a receptor related to vertebrate kisspeptin receptors.
- Phylogenetic analysis suggests inhibitory kisspeptin signaling evolved uniquely in Ambulacraria or was lost in chordates.

## Abstract

The neurohormone kisspeptin regulates reproductive maturation and function in mammals by stimulating hypothalamic production and release of gonadotropin-releasing hormone. However, little is known about kisspeptin-type neuropeptide function in invertebrates and the evolution of kisspeptin signalling as a regulator of physiological processes. Here, we address these issues in a deuterostome invertebrate — the starfish Asterias rubens (phylum Echinodermata).

Unlike mammals that have one kisspeptin precursor protein, in A. rubens, two precursor proteins (ArKPP1, ArKPP2) give rise to four kisspeptin-type neuropeptides (ArKP1.1, ArKP1.2, ArKP2.1, ArKP2.2). Use of mRNA in situ hybridisation and immunohistochemistry revealed widespread but different patterns of expression of KP1-type and KP2-type neuropeptides in the central nervous system, locomotory organs, sensory organs, reproductive system, and digestive system of A. rubens. In vitro experiments revealed that KP1-type and KP2-type neuropeptides have opposing myoinhibitory and myoexcitatory effects, respectively, on starfish gonad and stomach preparations. When injected in vivo, both KP1-type and KP2-type neuropeptides trigger stomach eversion and ArKP1.2 affects righting behaviour.

This study has revealed that kisspeptin-type neuropeptides are evolutionarily ancient and pleiotropic regulators of processes that extend beyond reproductive physiology. Furthermore, the excitatory actions of ArKP2.2 in A. rubens are consistent with stimulatory effects of kisspeptins in vertebrates; accordingly, ArKP2.2 acts as a ligand for a receptor (ArKPR3) that is closely related to vertebrate kisspeptin receptors. On the other hand, phylogenetic analysis of receptors for ArKP1.1 and ArKP1.2 indicates that inhibitory kisspeptin signalling either evolved uniquely in Ambulacraria (echinoderms, hemichordates) or originated in Urbilateria but was lost in chordates.

The online version contains supplementary material available at 10.1186/s12915-026-02555-1.