Identification of a Novel Neuromedin U Receptor Subtype Expressed in the Central Nervous System

Abstract

Neuromedin U is a neuropeptide prominently expressed in the upper gastrointestinal tract and central nervous system. Recently, GPR66/FM-3 (NmU-R1) was identified as a specific receptor for neuromedin U. A BLAST search of the GenBank TM genomic database using the NmU-R1 cDNA sequence revealed a human genomic fragment encoding a G protein-coupled receptor that we designated NmU-R2 based on its homology to NmU-R1. The full-length NmU-R2 cDNA was subsequently cloned, stably expressed in 293 cells, and shown to mobilize intracellular calcium in response to neuromedin U. This response was dose-dependent (EC 50 ‫؍‬ 5 nM) and specific in that other neuromedins did not induce a calcium flux in receptor-transfected cells. Expression analysis of human NmU-R2 demonstrated its mRNA to be most highly expressed in central nervous system tissues. Based on these data, we conclude that NmU-R2 is a novel neuromedin U receptor subtype that is likely to mediate central nervous system-specific neuromedin U effects.

Localisation of NMU1R and NMU2R in human and rat central nervous system and effects of neuromedin-U following central administration in rats

“…Whilst these data are in general agreement with other recent reports of NMU2R mRNA distribution shown using RT-PCR Raddatz et al 2000), Northern analysis (Howard et al 2000;Shan et al 2000) and in situ hybridisation (Howard et al 2000), here we show a more diverse brain expression of NMU2R mRNA. There were higher CNS levels of expression of NMU2R in all 18 human regions tested.…”

“…A second receptor for NmU, the novel orphan receptor FM-4 (Howard et al 2000), was subsequently described by several groups (Howard et al 2000;Shan et al 2000;Hosoya et al 2000;Raddatz et al 2000). In agreement, each group reported an EC 50 of 1-5 nM for activation of FM-4 by NmU in functional assays measuring Ca 2+ mobilisation.…”

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

“…In a similar way to NmU, the C-terminal regions of NMUR1 and NMUR2 are highly conserved across different species and appear to be determinant for biological activity (40 ). In fact, NMUR1 and NMUR2 share significant sequence homology, suggesting that they arose as a duplication of an ancestral gene (39 ). Both receptors appear to bind with similar affinity to different forms of NmU.…”

“…Two different receptors exist for NmU, termed NMUR1 (also known as GPR66 and FM-3) and NMUR2 (also known as TGR-1 and FM-4), encoded by genes located in human chromosomes 2 and 5, respectively (14,28,29,(35)(36)(37)(38)(39). These receptors were identified from orphan class A G-protein-coupled receptors (GPCRs), possessing 7 transmembrane domains.…”

Neuromedin U Type 1 Receptor Stimulation of A-type K+ Current Requires the βγ Subunits of Go Protein, Protein Kinase A, and Extracellular Signal-regulated Kinase 1/2 (ERK1/2) in Sensory Neurons

“…This peptide acting through its receptor has been implicated in regulating a variety of physiological functions, including stress response, energy homeostasis, and nociception (2). Two G protein-coupled receptors including NMU type 1 receptor (NMUR1) and NMUR2 have been identified as the endogenous receptors for NMU (3,4). NMUR1 is expressed more abundantly in peripheral tissues, whereas NMUR2 is localized more centrally.…”