The evolution and functional significance of neuropeptide cocktails: insights from SALMFamides in asteroid...

Neuropeptides derived from larger precursor proteins are neuronal signalling molecules that regulate physiological processes and behaviour. Some precursors, particularly in invertebrates, give rise to 'cocktails' of structurally related neuropeptides, but the functional significance of this phenomenon is poorly understood. Here, we investigate this by analysing the evolution and receptor pharmacology of SALMFamide-type neuropeptides in starfish (class Asteroidea, phylum Echinodermata). Two types of SALMFamide precursors occur in echinoderms: L-type and F-type, which contain neuropeptides that typically have C-terminal LxF-NH2 and FxF-NH2 motifs (x is variable), respectively. In starfish, L-type and F-type precursors typically contain seven and nine neuropeptides, respectively, but taxon-specific loss/gain of neuropeptides has occurred. Experimental tests revealed that most neuropeptides derived from L-type and F-type precursors in the starfish Asterias rubens exhibit similar potency/efficacy as ligands for their kisspeptin-type receptors, ArKPR7 and ArKPR6, respectively. However, the N-terminally positioned neuropeptide in each precursor has lower potency/efficacy. Furthermore, one neuropeptide derived from the F-type precursor exhibits convergent similarity with L-type precursor-derived neuropeptides, but it has low potency as a ligand for ArKPR7. Our findings indicate that structurally related neuropeptides derived from the same precursor are functionally redundant as receptor ligands; therefore, loss of neuropeptides and/or neuropeptide bioactivity can occur.