Species‐dependent smooth muscle contraction to Neuromedin U and determination of the receptor subtypes mediating contraction using NMU1 receptor knockout mice

Abstract

1 The peptide ligand neuromedin U (NMU) has been implicated in an array of biological activities, including contraction of uterine, intestinal and urinary bladder smooth muscle. However, many of these responses appear to be species-specific. This study was undertaken to fully elucidate the range of smooth muscle-stimulating effects of NMU in rats, mice and guinea-pigs, and to examine the extent of the species differences. In addition, the NMU1 receptor knockout mouse was used to determine which receptor subtype mediates the contractile responses generated by NMU in the mouse. 2 A range of isolated organ in vitro bioassays were carried out, which were chosen to re-confirm previous literature reports (uterine and stomach fundus contraction) and also to explore potentially novel smooth muscle responses to NMU. This investigation uncovered a number of previously unidentified NMU-mediated responses: contraction of rat lower esophageal sphinster (LES), rat ileum, mouse gallbladder, enhancement of electrically evoked contractions in rat and mouse vas deferens, and a considerable degree of cross-species differences. 3 Studies using the NMU1 receptor knockout mice revealed that in the mouse fundus and gallbladder assays the NMU contractile response was mediated entirely through the NMU1 receptor subtype, whereas, in assays of mouse uterus and vas deferens, the response to NMU was unchanged in the NMU1 receptor knockout mouse, suggesting that the NMU response may be mediated through the NMU2 receptor subtype. NMU receptor subtype-selective antagonists are required to further elucidate the role of the individual receptor subtypes.

Paradoxical Behavior of Neuromedin U in Isolated Smooth Muscle Cells and Intact Tissue

“…This lack of functional desensitization was apparent irrespective of the interval between applications and at least with a 30-min interval allowed noncumulative concentration-response curves to be constructed with individual tissue strips. The potency of NmU (pEC 50 values, 7.5-7.8) is consistent with its potency in other gastrointestinal smooth muscle preparations of the rat (pEC 50 values, 6.4 -8.4;Prendergast et al, 2006). A clear paradox in the present study is the ability of NmU to mediate repetitive contractions of colonic smooth muscle strips but an inability to mediate repetitive Ca 2ϩ transients in cultured colonic smooth muscle cells.…”

“…Of relevance to the present study are the observations that NmU mediates contraction of canine (Westfall et al, 2001) and human colon (Jones et al, 2006) but not colon from rat, guinea pig, or mouse (Benito-Orfila et al, 1991;Prendergast et al, 2006). The lack of a direct effect of NmU on contraction of mouse colon has been supported by a recent study, although it did potently enhance electrically stimulated, nerve-evoked contractions, possibly through prejunctional effects within the enteric ganglia (Dass et al, 2007).…”

“…Subsequent characterization of NmU from human, rabbit, dog, frog, rat, and chicken has revealed a remarkable degree of structural homology, with identical C-terminal pentapeptides containing elements essential for biological activity (for review, see Brighton et al, 2004a). Physiologically, NmU has been implicated in smooth muscle contraction (Minamino et al, 1985;Maggi et al, 1990;Westfall et al, 2001;Prendergast et al, 2006;Dass et al, 2007); regulation of regional blood flow and blood pressure (Gardiner et al, 1990); the function and development of the pituitary-adrenal-cortical axis (Malendowicz et al, 1993); arterial pressure and heart rate (Westfall et al, 2001;Chu et al, 2002); stress (Hanada et al, 2001;Zeng et al, 2006); pronociception Yu et al, 2003); food intake and body weight (Howard et al, 2000;Kojima et al, 2000;Nakazato et al, 2000;Ivanov et al, 2002;Wren et al, 2002;Jethwa et al, 2005); gross locomotor activity, body temperature, heat production, and oxygen consumption (Howard et al, 2000;Nakazato et al, 2000); cancer (Yamashita et al, 2002); and the circadian oscillator (Nakahara et al, 2004) (for review, see Brighton et al, 2004a).…”

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

“…Our observation that NMU is expressed by neurons from thoracic DRG suggests that the coordinated action of neurons and chemosensory cells could promote tissue-based, ILC-dependent type 2 immune responses. Given the importance of smooth muscle contraction in the clinical manifestations of allergic diseases, it is intriguing that NMU can induce both smooth muscle contraction 44 and ILC2-driven inflammation. Neuronal activation following inhalation of noxious substances or allergens could potentially trigger both processes, simultaneously promoting physical expulsion and allergic immunity to the provoking stimulus.…”

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

“…A direct, dose-dependent contractile effect of NmU has been detected for different organs and tissues of the gastrointestinal and genitourinary tracts, and an indirect, enhancing effect of electrically induced contraction has also been identified, suggesting that NmU can act as a direct contraction inducer or as a potentiator of another contraction stimulus (49 -54 ). Studies with mice deficient in NmU receptors have shown that gastrointestinal smooth muscle contraction is likely mediated by NMUR1, because contraction is unaffected in Nmur2 Ϫ/Ϫ mice but compromised in Nmur1 Ϫ/Ϫ mice (53,54 ). On the contrary, genitourinary tract contraction appears to involve both receptors, although compensatory effects in the absence of one receptor cannot be ruled out.…”