Identification and Characterization of Two Neuromedin U Receptors Differentially Expressed in Peripheral Tissues and the Central Nervous System

Abstract

Two structurally related, G-protein-coupled receptors were identified as receptors for the neuropeptide, neuromedin U. This peptide is found in highest levels in the gut and genitourinary system where it potently contracts smooth muscle but is also expressed in the spinal cord and discrete regions of the brain. Binding sites for neuromedin U have been characterized in rat uterus, however, little is known about the activity of this peptide in the regions of the central nervous system where it is expressed. The receptors characterized in this report are activated by neuromedin U at nanomolar potency in heterologous expression systems and bind radiolabeled neuromedin U with high affinity. Localization of the receptor RNA by quantitative reverse transcription-polymerase chain reaction in a variety of human tissues shows distinct expression patterns for the two receptors. NMU1 is expressed predominantly in peripheral tissues, whereas NMU2 is more highly expressed in the central nervous system. Identification of neuromedin U receptor subtypes will greatly aid in the determination of the physiological roles of this peptide.

Effects of neuromedin-U on immature rat adrenocortical cells: In vitro and in vivo studies

“…Our present RT-PCR and ICC studies clearly demonstrate the expression of NMUR1 as mRNA and protein in the cortex of immature rat adrenals, thereby confirming earlier findings obtained in adult animals (9,(27)(28)(29)33,34). Moreover, the detection of NMUR1 mRNA in dispersed zona glomerulosa and zona fasciculata-reticularis cells rules out the possibility that the expression was due to the presence in the specimens assayed of the non-parenchymal components of the gland (connective tissue and capillaries).…”

“…NPY, cholecystokinin, galanin, leptin, orexins, beacon and NPW) (11)(12)(13)(14)(15)(16)(17), also NMU appears to regulate the hypothalamic-pituitary-adrenal (HPA) axis. The expression of NMU and NMUR 2 was found in the hypothalamus and anterior pituitary (10,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), while in the adrenal glands only the expression of NMUR1 was detected (9,(27)(28)(29)33,34). NMU has been shown to enhance c-fos expression in the hypothalamic paraventricular nucleus (1,2,30,35), to increase CRH and vasopressin output from rat hypothalamic explants, and to stimulate ACTH and corticosterone secretion in the rat (2,4,5,(36)(37)(38).…”

“…8). NMU acts via two subtypes of G protein-coupled receptors, NMUR1 and NMUR2, the former being the peripheral receptor and the latter the central one (9,10).…”

Comparison of feeding suppression by the anorexigenic hormones neuromedin U and neuromedin S in rats

“…NMUR1 (formerly FM-3/GPR66) is located in a wide range of peripheral tissues, such as intestine, testis, pancreas, uterus, lung, and kidney. In contrast, expression of NMUR2 (formerly FM-4/TGR-1) is limited to areas of the brain such as the paraventricular nucleus (PVN) along the wall of the third ventricle in the hypothalamus and the CA1 region of the hippocampus (Howard et al 2000, Raddatz et al 2000, Guan et al 2001, Graham et al 2003.…”

“…Thus far, the only known physiological role of NMU is contraction of smooth muscles in blood vessels, the uterus, and the gastrointestinal tract (Minamino et al 1985). Two G-protein-coupled receptors (NMUR1 and NMUR2) are thought to bind to NMU and mediate its physiological effects , Hedrick et al 2000, Howard et al 2000, Raddatz et al 2000, Szekeres et al 2000. NMUR1 (formerly FM-3/GPR66) is located in a wide range of peripheral tissues, such as intestine, testis, pancreas, uterus, lung, and kidney.…”