The first buccalin receptor identified in a mollusk responds to the same peptide family as human kisspeptin, revealing a shared evolutionary origin spanning hundreds of millions of years.
23–320 nMEC50 range for 19 buccalin peptides activating the first identified mollusk buccalin receptor
What the researchers found
Researchers identified the first buccalin receptor in the sea slug Aplysia californica, designated apBuc/AstA-R. All 19 mature buccalin peptides activated this G protein-coupled receptor in a dose-dependent manner, with EC50 values ranging from 23 to 320 nM.
Critically, the study found cross-activity: fruit fly allatostatin A peptides and human kisspeptin could also activate this Aplysia receptor, while human galanin could not. This supports the hypothesis that the mollusk buccalin/allatostatin A signaling system is evolutionarily related to the mammalian galanin and kisspeptin systems — peptide families important in reproduction, metabolism, and appetite.
Why it matters
Understanding how neuropeptide signaling systems evolved across species helps researchers trace the origins of peptides that are important in human health. Kisspeptin controls reproduction and galanin influences appetite and pain — knowing their evolutionary roots in ancient mollusk peptides could reveal conserved mechanisms and potential new drug targets.
The numbers in context
19 buccalin peptides tested · EC50 range: 23–320 nM · Cross-activation by Drosophila AstA and human kisspeptin · No activation by human galanin
How the study worked
The researchers used bioinformatics to identify candidate buccalin receptors in the Aplysia genome, then cloned the receptor and tested it in cell-based assays. They measured dose-response activation with all 19 buccalin peptides and tested cross-reactivity with fruit fly allatostatin A peptides and human kisspeptin and galanin. Phylogenetic and chromosomal analyses were used to map evolutionary relationships.
Who was studied
Aplysia californica (sea slug) — cell-based receptor assays
What this study cannot tell us
This is a basic biology study in an invertebrate model (sea slug). The evolutionary connections to human kisspeptin and galanin systems, while supported by phylogenetic analysis, are inferred rather than functionally proven in mammalian systems. The KISSR-like receptor found in Aplysia could not be activated by any tested peptides, leaving its function unknown.
How to read the evidence
This is basic research characterizing a receptor in an invertebrate model organism. While it provides important evolutionary insights, the findings are far removed from direct human clinical relevance.
When this study was published
Published in 2025. This is a very recent contribution to the evolutionary understanding of neuropeptide signaling systems.
The bigger picture
This work connects peptide signaling in invertebrates to clinically relevant peptide systems in humans. Kisspeptin is central to puberty and fertility, while galanin modulates pain, appetite, and cognition. Tracing their origins to ancient buccalin-type peptides in mollusks deepens our understanding of how these signaling systems arose and diversified — knowledge that could inform peptide drug design by revealing conserved receptor mechanisms.
Questions still open
- Could the conserved receptor mechanisms between buccalin and kisspeptin systems reveal new drug targets for reproductive disorders?
- What is the function of the KISSR-like receptor found in Aplysia that could not be activated by any tested peptide?
- How might the evolutionary split between galanin and kisspeptin signaling inform our understanding of metabolic versus reproductive peptide pathways?
Common questions
What is buccalin and why does it matter?
How does a sea slug study relate to human health?
Read the original research
Identification of a G Protein-Coupled Receptor for Buccalin-Type Peptides in the Mollusk Aplysia: Evolutionary Insights into Neuropeptide Signaling.
ACS omega, 10(39), 45073-45089
Citation
Xu, Ju-Ping; Ding, Xue-Ying; Jin, Qing-Chun; Zhang, Yi-Long; Chang, Jian-Hui; Jiang, Hui-Min; Li, Ya-Dong; Fu, Ping; Zhang, Yan-Chu-Fei; Liu, Cui-Ping; Mao, Rui-Ting; Liu, Cheng-Yi; Li, Fan; Wu, Shao-Qian; Cropper, Elizabeth C; Zhang, Guo; Jing, Jian. (2025). Identification of a G Protein-Coupled Receptor for Buccalin-Type Peptides in the Mollusk Aplysia: Evolutionary Insights into Neuropeptide Signaling.. ACS omega, 10(39), 45073-45089. https://doi.org/10.1021/acsomega.5c03789