Neuromedin U (NMU) is a neuropeptide that is expressed in the gastrointestinal tract and central nervous system. NMU interacts with two G protein–coupled receptors, NMU-R1 and NMU-R2. Whereas NMU-R2 localizes predominantly to nerve cells, NMU-R1 is expressed in peripheral tissues including lymphocytes and monocytes, suggesting a role of NMU in immunoregulation. However, the functions of NMU in peripheral tissues have not been clarified. In this study, using NMU-deficient mice, we first demonstrated that NMU plays an important role in mast cell-mediated inflammation. Complete Freund's adjuvant-induced mast cell degranulation as well as edema and neutrophil infiltration, which occurred weakly in mast cell–deficient WBB6F1-W/W v mice, did not occur in NMU-deficient mice. Moreover, intraplantar injection of NMU into paws induced early inflammatory responses such as mast cell degranulation, vasodilation, and plasma extravasation in WT mice but not in WBB6F1-W/W v mice. NMU-R1 was highly expressed in primary mast cells, and NMU induced Ca2+ mobilization and degranulation in peritoneal mast cells. These data indicate that NMU promotes mast cell–mediated inflammation; therefore, NMU receptor antagonists could be a novel target for pharmacological inhibition of mast cell–mediated inflammatory diseases.

Neuromedin U (NMU) is a neuropeptide expressed not only in the central nervous system but also in various organs, including the gastrointestinal tract and lungs. NMU interacts with two G protein-coupled receptors, NMU-R1 and NMU-R2. Although NMU-R2 is expressed in a specific region of the brain, NMU-R1 is expressed in various peripheral tissues, including immune and hematopoietic cells. Our recent study demonstrated an important role of NMU in mast cell-mediated inflammation. In this study, we showed that airway eosinophilia was reduced in NMU-deficient mice in an allergen-induced asthma model. There were no differences in the antigen-induced Th2 responses between wild-type and NMU knockout mice. NMU-R1 was highly expressed in the eosinophil cell line, and NMU directly induced Ca(2+) mobilization and extracellular/signal-regulated kinase phosphorylation. NMU also induced cell adhesion to components of the extracellular matrix (fibronectin and collagen type I), and chemotaxis in vitro. Furthermore, NMU-R1 was also expressed in human peripheral blood eosinophils, and NMU induced cell adhesion in a dose-dependent manner. These data indicate that NMU promotes eosinophil infiltration into inflammatory sites by directly activating eosinophils. Our study suggests that NMU receptor antagonists could be novel targets for pharmacological inhibition of allergic inflammatory diseases, including asthma.

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J. Neurochem. (2010) 113, 1046–1059. Abstract Studies in animal models of Parkinson’s disease have revealed that degeneration of noradrenaline neurons is involved in the motor deficits. Several types of adrenoceptors are highly expressed in neostriatal neurons. However, the selective actions of these receptors on striatal signaling pathways have not been characterized. In this study, we investigated the role of adrenoceptors in the regulation of dopamine/dopamine‐ and cAMP‐regulated phosphoprotein of Mr 32 kDa (DARPP‐32) signaling by analyzing DARPP‐32 phosphorylation at Thr34 [protein kinase A (PKA)‐site] in mouse neostriatal slices. Activation of β1‐adrenoceptors induced a rapid and transient increase in DARPP‐32 phosphorylation. Activation of α2‐adrenoceptors also induced a rapid and transient increase in DARPP‐32 phosphorylation, which subsequently decreased below basal levels. In addition, activation of α2‐adrenoceptors attenuated, and blockade of α2‐adrenoceptors enhanced dopamine D1 and adenosine A2A receptor/DARPP‐32 signaling. Chemical lesioning of noradrenergic neurons mimicked the effects of α2‐adrenoceptor blockade. Under conditions of α2‐adrenoceptor blockade, the dopamine D2 receptor‐induced decrease in DARPP‐32 phosphorylation was attenuated. Our data demonstrate that β1‐ and α2‐adrenoceptors regulate DARPP‐32 phosphorylation in neostriatal neurons. Gi activation by α2‐adrenoceptors antagonizes Gs/PKA signaling mediated by D1 and A2A receptors in striatonigral and striatopallidal neurons, respectively, and thereby enhances D2 receptor/Gi signaling in striatopallidal neurons. α2‐Adrenoceptors may therefore be a therapeutic target for the treatment of Parkinson’s disease.

Close observation and prompt counteractions including termination of one-lung ventilation (OLV) are crucial for patients under OLV in the supine position, because life-threatening hypoxemia frequently occurs approximately 10 min after starting OLV, even under 100% oxygen inhalation. The left semilateral decubitus position was as effective as the left lateral decubitus position in avoiding life-threatening hypoxemia during OLV.

Laser Doppler flowmetry (LDF) was conducted on familial amyloidotic polyneuropathy (FAP) patients and asymptomatic carriers of FAP. Vasoconstrictive responses in the 11 FAP patients tested, induced by deep inspiration, were markedly depressed compared with those of the healthy controls. The responses decreased with the progression of FAP, with no responses being elicited from the 7 patients in stages 2 (moderate) to 4 (terminal). Interestingly, vasoconstrictive responses following deep inspiration also were depressed in 3 of 4 asymptomatic carriers of FAP who showed no clinical sign of FAP, and who had normal sensory nerve conduction velocity. Patients who had such diseases as Shy-Drager's disease, spinocelebellar degeneration, and pandysautonomia showed no decrease in blood flow for various stimulations. In contrast, patients with primary amyloidosis, who had no autonomic dysfunction, showed a normal pattern. Detection of the autonomic functions in FAP patients and asymptomatic carriers by capsule polyhydrography and computer analysis of the cardiographic R-R interval revealed that the asymptomatic carriers of FAP, as well as the FAP patients, had disordered peripheral autonomic functions. Our results suggest that the autonomic nervous system is first affected during the very early stage of FAP.

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