Unanticipated Characteristics of a Selective, Potent Neuromedin-U Receptor 2 Agonist

Abstract

Neuromedin-U (NMU) mediates several physiological functions via its two cognate receptors, NMUR1 and NMUR2. Disentangling the individual roles of each receptor has largely been undertaken through the use of transgenic mice bearing a deletion in one of the two receptors or by testing native molecules (NMU or its truncated version NMU-8) in a tissuespecific manner, in effect, taking advantage of the distinct receptor expression profiles. These strategies have proved quite useful despite the inherent limitations of overlapping receptor roles and potential compensatory influences of germline gene deletion. With these considerations in mind, the availability of potent, selective NMU compounds with appropriate pharmacokinetic profiles would advance the capabilities of investigators undertaking such efforts. Here, we evaluate a recently reported NMUR2-selective peptide (compound 17) for its in vitro potency (mouse and human), binding affinity, murine pharmacokinetic properties, and in vivo effects. Despite being designed as an NMUR2 agonist, our results show compound 17 unexpectedly binds but does not have functional activity on NMUR1, thereby acting as an R1 antagonist while simultaneously being a potent NMUR2 agonist. Furthermore, evaluation of compound 17 across all known and orphan G-protein-coupled receptors demonstrates multiple receptor partners beyond NMUR2/R1 binding. These properties need to be appreciated for accurate interpretation of results generated using this molecule and may limit the broader ability of this particular entity in disentangling the physiological role of NMU receptor biology.

Effects of non‐nutritive sweeteners on growth and intestinal health by regulating hypothalamic RNA profile and ileum microbiota in guinea pigs

“…One previous study has identified TPH2 and NMU as neuropeptides that suppress appetite 45 . Neuromedin U was initially isolated from porcine spinal cord and subsequently found in mammals, 46 birds, 22 amphibians, 47 and fish 48 . It may exert anorexic effects by upregulating corticotropin‐releasing hormone and arginine‐angiotensin in the central nervous system 49 .…”

Drosophila melanogaster Limostatin and Its Human Ortholog Promote West Nile Virus Infection

“…In human innate immunity, it is possible that disruption of the NMU pathway would lead to protection from WNV infection in pancreatic β-cells and other cell types, as well as other mammalian models. A known antagonist of NMU signaling has been identified [ 74 ]. However, disruption of NMU activity may have adverse side effects.…”