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Activation of Bombesin Receptor Subtype-3 Influences Activity of Orexin Neurons by Both Direct and Indirect Pathways

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Activation of Bombesin Receptor Subtype-3 Influences Activity of Orexin Neurons by Both Direct and Indirect Pathways J Mol Neurosci (2010) 42:106–111 DOI 10.1007/s12031-010-9382-5 Activation of Bombesin Receptor Subtype-3 Influences Activity of Orexin Neurons by Both Direct and Indirect Pathways Naoki Furutani & Mari Hondo & Natsuko Tsujino & Takeshi Sakurai Received: 31 March 2010 /Accepted: 20 April 2010 /Published online: 14 May 2010 # Springer Science+Business Media, LLC 2010 Abstract The neuropeptides orexin A and orexin B (also BRS3 might be an important pathway for regulation of known as hypocretin 1 and hypocretin 2), produced in feeding and sleep/wake states. This pathway might serve as lateral hypothalamic neurons, are critical regulators of a novel target for the treatment of obesity. feeding behavior, the reward system, and sleep/wake states. Orexin-producing neurons (orexin neurons) are regulated Keywords Orexin . BRS3 . Patch clamp . Calcium by various factors involved in regulation of energy imaging . Food intake . Sleep homeostasis and sleep/wakefulness states. Bombesin recep- tor subtype 3 (BRS3) is an orphan receptor that might be implicated in energy homeostasis and is highly expressed in Introduction the hypothalamus. However, the neural pathway by which BRS3 regulates energy homeostasis is largely unknown. The neuropeptides orexin A and orexin B were identified as We examined whether BRS3 is involved in the regulation endogenous ligands for two orphan G-protein-coupled of orexin neurons. Using a calcium imaging method, we receptors (GPCRs) (Sakurai et al. 1998). Orexin-producing found that a selective BRS3 agonist [Ac-Phe-Trp-Ala-His- neurons (orexin neurons) are localized exclusively in the (τBzl)-Nip-Gly-Arg-NH2] increased the intracellular calci- lateral hypothalamic area (LHA), which is known as the um concentration of orexin neurons. However, intracellular feeding center. Various evidence has suggested that this recordings from slice preparations revealed that the BRS3 neuropeptide is involved in the regulation of feeding agonist hyperpolarized orexin neurons. The BRS3 agonist behavior (Sakurai et al. 1998; Edwards et al. 1999; Haynes depolarized orexin neuron in the presence of tetrodotoxin. et al. 2000; Haynes et al. 2002). Subsequently, the finding Moreover, in the presence of GABA receptor blockers, that orexin deficiency causes narcolepsy in humans and picrotoxin and CGP55845, the BRS3 agonist induced animals suggested that these hypothalamic neuropeptides depolarization and increased firing frequency. Additionally, also play a critical role in regulating sleep and wakefulness double-label in situ hybridization study revealed that Brs3 (Chemelli et al. 1999; Lin et al. 1999; Peyron et al. 2000; mRNA was expressed in almost all orexin neurons and Thannickal et al. 2000; Hara et al. 2001). many cells around these neurons. These findings suggest Recent studies of the efferent and afferent systems of that the BRS3 agonist indirectly inhibited orexin neurons orexin-producing neurons, as well as phenotypic character- through GABAergic input and directly activated orexin ization of mice with genetic alterations in the orexin system, neurons. Inhibition of activity of orexin neurons through have suggested further roles of orexin in the coordination of emotion, energy homeostasis, reward, drug addiction, and This manuscript is related to the Yakushima 2009 symposium arousal. Orexin neurons receive abundant input from the N. Furutani : M. Hondo : N. Tsujino : T. Sakurai (*) limbic system, preoptic sleep-promoting neurons, and hypo- Department of Molecular Neuroscience and Integrative thalamic neurons implicated in energy homeostasis. Orexin Physiology, Faculty of Medicine, neurons are also regulated by peripheral metabolic cues, Kanazawa University, including ghrelin, leptin, and glucose, suggesting that orexin 13-1 Takaramachi, Kanazawa-shi, Ishikawa 920-8640, Japan neurons might provide a link between energy homeostasis and e-mail: [email protected] sleep/wake states (Yamanaka et al. 2003b). J Mol Neurosci (2010) 42:106–111 107 Bombesin receptor subtype 3 (BRS3) is a member of the Animals bombesin receptor subfamily of GPCRs, which also includes the neuromedin B- and gastrin-releasing peptide receptors All experimental procedures involving animals were ap- (NMBR and GRPR) (Gorbulev et al. 1992). BRS3 couples to proved by the Kanazawa University Animal Care and Use endogenous Gq family proteins and increases intracellular Committee and were in accordance with NIH guidelines. calcium concentration. BRS3 has a unique pharmacological All efforts were made to minimize animal suffering and profile and does not bind with high affinity with any known discomfort and to reduce the number of animals used. bombesin-related peptides. Although a number of molecules Genetically modified mice used in this study were Orexin/ that can activate human BRS3 have been developed (Mantey YC2.1 mice (Tsujino et al. 2005) and Orexin/EGFP mice et al. 1997; Liu et al. 2002; Weber et al. 2003; Boyle et al. (Yamanaka et al. 2003a). 2005;Gonzalezetal.2008; Zhang et al. 2009), its natural ligands are still unknown (Jensen et al. 2008). In Situ Hybridization BRS3 is primarily expressed in the CNS and is present in the highest amounts in the hypothalamic area where orexin Double in situ hybridization was performed according to neurons are localized (Ohki-Hamazaki et al. 1997a; Yamada procedures previously described (Mieda et al. 2006). et al. 1999; Liu et al. 2002; Jennings et al. 2003; Sano et al. Digoxigenin (DIG)-labeled riboprobes for mBrs3 were 2004). Although the normal physiological function of BRS3 synthesized from a 1196-bp fragment of murine Brs3 is largely unknown, mice lacking the BRS3 gene develop cDNA (nucleotides −172 to +1367 from the initiation codon) late onset obesity, accompanied by a reduced metabolic rate containing 1196 bp of the whole coding region cloned into the and increased food intake (Ohki-Hamazaki et al. 1997b). In pCRII vector (Invitrogen). Fluorescein (FITC)-labeled ribop- good agreement with the Brs3−/− mouse study, a BRS3 robes for prepro-Orexin were synthesized by in vitro agonist, Bag-1, reduced food intake and increased metabolic transcription. pBluescript II SK (+) containing a 0.5-kb rate (Guan et al. 2010). These studies suggested that BRS3 fragment encoding Gln-33–Val-130 of prepro-Orexin was might be an important regulator of feeding behavior and used as a template for in vitro transcription (Sakurai et al. energy homeostasis. A recent study showed that the 1998). The DIG- and FITC-labeled probes were detected by anorectic effects of the BRS3 agonist remained intact in means of anti-DIG (1/2000) and anti-FITC (1/1000) anti- neuropeptide Y−/−, agouti-related peptide−/−, melanocortin bodies conjugated with alkaline phosphatase (Roche Diag- 4receptor−/−, cannabinoid receptor 1−/−,andleptin nostics, Basel, Switzerland). Alkaline phosphatase activity receptordb/db mice (Guan et al. 2010). These results suggest was detected with NBT/BCIP and INT/BCIP (Roche that the effect of the BRS3 agonist might be mediated Diagnostics). through other feeding mechanisms. However, the neural pathways of feeding behavior mediated by BRS3 are largely Brain Slice Preparation undefined. The orexin pathway is one of the possible pathways by which the BRS3 agonist evokes its effects, Orexin/YC2.1 mice (3–8 weeks old) and Orexin/EGFP mice because orexin neurons are regulated by several factors (3–6 weeks old) were anesthetized with forane (Abbott, involved in energy metabolism, and expression of BRS3 Osaka, Japan). The mice were decapitated under deep were found in the LHA. To investigate this possibility, we anesthesia. Brains were isolated in ice-cold cutting solution evaluated the effect of a BRS3 agonist on orexin neurons. In consisting of (in millimolar): 280 sucrose, 2 KCl, 10 HEPES, this study, we found that a BRS3 agonist activated orexin 0.5 CaCl2,10MgCl2, and 10 glucose, pH 7.4, bubbled with neurons directly, while it also inhibited these neurons 100% O2. Brains were cut coronally into 300-μmsliceswith through activation of local GABAergic interneurons. a vibratome (VTA-1000S, Leica, Germany). Slices contain- ing the LHA were transferred for 1 h to an incubation chamber at room temperature filled with physiological Materials and Methods solution containing (in millimolar): 125 NaCl, 2.5 KCl, 1.25 NaH2PO4, 2.0 CaCl2,1.0MgSO4,26NaHCO3,and11 Drugs glucose, pH 7.4, bubbled with 95% O2/5% CO2. The BRS3 agonist, neuromedin B (Peptide Institute, Osaka, Calcium Imaging of Orexin Neurons Japan), tetrodotoxin (TTX) (Wako, Osaka, Japan), picro- toxin (Sigma, St. Louis, MO), and CGP55845 (Wako) were Optical recordings were performed on a fluorescence dissolved in extracellular solution. We also used a synthe- microscope (BX51WI, Olympus, Tokyo, Japan) equipped sized a selective BRS3 agonist [Ac-Phe-Trp-Ala-His with a cooled charge-coupled device (CCD) camera (Cool- (τBzl)-Nip-Gly-Arg-NH2] (Boyle et al. 2005). SNAP HQ2, Roper Scientific, Tucson, AZ) controlled by 108 J Mol Neurosci (2010) 42:106–111 MetaFluor 5.0.7 software (Universal Imaging, West Chester, slice. A tight seal of 0.5–1.0 GΩ was made by applying PA). YC2.1 was excited through a 440DF20 filter, and its negative pressure. The membrane patch was then fluorescent image was subjected to dual emission ratio ruptured by suction. The series resistance during record- imaging through two emission filters (480DF30 for ECFP, ing was 10–25 MΩ and was compensated. The reference 535DF26 for EYFP) controlled by a filter changer (ProscanII, electrode was an Ag–AgCl pellet
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