The ghrelin receptor GHSR has two efficient agonists in an ancient fish species

Abstract

AbstractThe gastric peptide ghrelin and its receptor GHSR have important functions in energy metabolism. Recently, liver-expressed antimicrobial peptide 2 (LEAP2) was identified as an endogenous antagonist for GHSR. Ghrelin, LEAP2, and GHSR are ubiquitously present from fishes to mammals and are highly conserved in evolution. However, our recent study suggested that GHSRs from the Actinopterygii fishDanio rerio(zebrafish) andLarimichthys crocea(large yellow croaker) have lost their binding to ghrelin, despite binding normally to LEAP2. Do these fish GHSRs use another peptide as their agonist? To answer this question, in the present study, we tested to two fish motilins that are closely related to ghrelin. In ligand binding and activation assays, the fish GHSRs fromD. rerioandL. croceadisplayed no detectable or very low binding to all tested motilins; however, the GHSR from the Sarcopterygii fishLatimeria chalumnae(coelacanth) bound to its motilin with high affinity and was efficiently activated by it. Therefore, it seemed that motilin is not a ligand for GHSR inD. rerioandL. crocea, but is an efficient agonist for GHSR inL. chalumnae, which is known as a ‘living fossil’ and is believed to be one of the closest fish ancestors of tetrapods. The results of present study suggested that in ancient fishes, GHSR had two efficient agonists, ghrelin and motilin; however, this feature might be only preserved in some extant fishes with ancient evolutionary origins. Our present work shed new light on the ligand usage of GHSR in different fish species and in evolution.