The cover image for the April 1 issue of Biophysical Journal depicts a common periwinkle (Littorina littorea) and an annelid worm (Malacoceros fuliginosus) pointing in opposing directions—an artistic representation of our recent findings on receptor-ligand interactions in similar species. This image was composed to symbolize the surprising “flip” in ligand orientation when the same ligand binds to closely related receptors in mollusks and annelids.

Our research explores how the H-Phe-Met-Arg-Phe-NH₂ (FMRFa)-gated sodium channels (FaNaCs) in these phyla recognize their neuropeptide ligand, FMRFa. Using mutagenesis and functional assays alongside existing structural data, we demonstrated that mollusk FaNaCs require the neuropeptide’s N terminus for activation, whereas annelid FaNaCs rely on the C terminus. This finding challenges assumptions that structurally similar receptors function in identical ways and opens new avenues for understanding receptor evolution and pharmacology. We are pursuing such themes in other projects, which can be followed at LynaghLab.com and https://www.uib.no/ en/michaelsarscentre.

Beyond our own projects, our findings have implications for the design of receptor-targeting compounds: by understanding how small structural changes affect ligand binding, researchers can develop more precise tools for modulating ion channels, which are crucial targets in neurobiology and medicine.

—Emily J.S. Claereboudt, Mowgli Dandamudi, Léa Longueville, Hassan Y. Harb, and Timothy Lynagh