Neuromedins NMU and NMS: An Updated Overview of Their Functions

Abstract

More than 35 years have passed since the identification of neuromedin U (NMU). Dozens of publications have been devoted to its physiological role in the organism, which have provided insight into its occurrence in the body, its synthesis and mechanism of action at the cellular level. Two G protein-coupled receptors (GPCRs) have been identified, with NMUR1 distributed mainly peripherally and NMUR2 predominantly centrally. Recognition of the role of NMU in the control of energy homeostasis of the body has greatly increased interest in this neuromedin. In 2005 a second, structurally related peptide, neuromedin S (NMS) was identified. The expression of NMS is more restricted, it is predominantly found in the central nervous system. In recent years, further peptides related to NMU and NMS have been identified. These are neuromedin U precursor related peptide (NURP) and neuromedin S precursor related peptide (NSRP), which also exert biological effects without acting via NMUR1, or NMUR2. This observation suggests the presence of another, as yet unrecognized receptor. Another unresolved issue within the NMU/NMS system is the differences in the effects of various NMU isoforms on diverse cell lines. It seems that development of highly specific NMUR1 and NMUR2 receptor antagonists would allow for a more detailed understanding of the mechanisms of action of NMU/NMS and related peptides in the body. They could form the basis for attempts to use such compounds in the treatment of disorders, for example, metabolic disorders, circadian rhythm, stress, etc.

Keywords: GPCR (G protein coupled receptor); NMUR1; NMUR2; NSRP; NURP; biologically active peptides; neuromedin S (NMS); neuromedin U (NMU).

Figure 1

Structure of human genes encoding ppNMU (A) and ppNMS (C) according to ENSEMBL database. The structure of individual genes or alternative splice variants and their positions on the chromosomes was visualized using “GenomicFeatures” and “Gviz” packages of the programming R language. Exons of protein-coding splice variants are marked in orange whilst grey color corresponds to exons of non-protein-coding splice variants. Colored squares mark the coding gene regions for NMU25, NMS, NURP and NSRP. Aminoacid sequence fragment of individual ppNMU variants encoding NMU25 or NURP were also visualized (B).

Figure 2

Schematic structure of preproNMU and preproNMS in humans and preproNMU and preproNMS derived peptides. Data from Protein Knowledgebase (UniProtKB) P48645 and Q5H8A3, respectively. Schematic structure of preproNMU is modified from Austin et al. (14). Numbers refer to residues and cleavage sites are given in blue. Authors of the first description of NURP and/or NSRP are shown (5, 8).

Figure 3

The expression of NMU, NMS, NMUR1 and NMUR2 genes in normal human tissues as assessed by RNAseq and microarray (MARR) methods. Data obtained from gene card analyses. GeneCards identifiers: NMU - GC04M055595; NMS - GC02P100453, NMUR1 - GC02M231572; NMUR2 - GC05M152391.

Figure 4

Expression levels (RPKM—reads per kilobase million) of NMU, NMS, NMUR1 and NMUR2 genes in adrenal, brain, muscle, testes and uterus of male and female rats of the Fischer strain in four developmental stages: juvenile (2 weeks), adolescence (6 weeks), adult (21 weeks) and aged (104 weeks) as demonstrated by RNA-seq. Color of the circle corresponds to the appropriate development stage. The analysis of data published by Yu et al. (46). Data was obtained from Gene Expression Omnibus database, accession number: GSE53960 (available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE53960) (accessed date: 4 April 2021).