Emerging pharmacology and physiology of neuromedin U and the structurally related peptide neuromedin S

Abstract

Neuromedin U (NMU) has been paired with the G-protein-coupled receptors (GPRs) NMU1 (formely designated as the orphan GPR66 or FM-3) and NMU2 (FM-4 or hTGR-1). Recently, a structurally related peptide, neuromedin S (NMS), which shares an amidated C-terminal heptapeptide motif, has been identified in both rat and human, and has been proposed as a second ligand for these receptors. Messenger RNA encoding NMU receptor subtypes shows differential expression: NMU1 is predominantly expressed in peripheral tissues, particularly the gastrointestinal tract, whereas NMU2 is abundant within the brain and spinal cord. NMU peptide parallels receptor distribution with highest expression in the gastrointestinal tract and specific structures within the brain, reflecting its major role in the regulation of energy balance. The NMU knockout mouse has an obese phenotype and, in agreement, the Arg165Trp amino acid variant of NMU-25 in humans, which is functionally inactive, co-segregated with childhood-onset obesity. Emerging physiological roles for NMU include vasoconstriction mediated predominantly via NMU1 with nociception and bone remodelling via NMU2. The NMU system has also been implicated in the pathogenesis of septic shock and cancers including bladder carcinoma and acute myeloid leukaemia. Intriguingly, NMS is more potent at NMU2 receptors in vivo where it has similar central actions in suppression of feeding and regulation of circadian rhythms to NMU. Taken together with its vascular actions, NMU may be a functional link between energy balance and the cardiovascular system and may provide a future target for therapies directed against the disorders that comprise metabolic syndrome.

Transcriptome profiling of 6-OHDA model of Parkinson’s disease

“…It may play an important role in energy metabolism, as it is involved in the processes of regulation of appetite. There is also evidence that this gene is involved in the pathogenesis of some cancers, such as lung cancer, bladder cancer, and myeloid leukemia [15]. We cannot exclude its participation in the pathogenesis of PD, as many of the functions of this protein remain unknown, and we were able to show a significant increase in its mRNA in the substantia nigra of rats with a Parkinson-like phenotype.…”

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

“…Expression in the brain is actually localized in discrete regions, which means that expression levels in the whole brain are quite low (20,22,26,27 ). The regions with highest NmU-LI are the anterior pituitary gland, striatum, hypothalamus, medulla oblongata, cingulate gyrus, and medial frontal gyrus, with lower expression levels in hypothalamus, locus coeruleus, thalamus, and substantia Conserved residues among species are highlighted in color, and the highly conserved C-terminus region is also highlighted as a whole.…”

Neuromedin U: A Candidate Biomarker and Therapeutic Target to Predict and Overcome Resistance to HER-Tyrosine Kinase Inhibitors

“…Evidence suggests a role for NmU in pain, stress, immunemediated inflammatory diseases, and feeding regulation (see reviews: refs. 22,23). A limited number of studies to date have associated NmU with cancer; with conflicting observations depending on the cancer type.…”