Activation of Bombesin Receptor Subtype-3 Influences Activity of Orexin Neurons by Both Direct and Indirect Pathways
Activation of Bombesin Receptor Subtype-3 Influences Activity of Orexin Neurons by Both Direct and Indirect Pathways
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DOI：
10.1007/s12031-010-9382-5
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发表时间：
2010-09-01
影响因子：
3.1
通讯作者：
Sakurai, Takeshi
中科院分区：
文献类型：
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作者：
Furutani, Naoki;Hondo, Mari;Sakurai, Takeshi
下丘脑外侧神经元产生的神经肽食欲素A和食欲素B（也称为下丘脑泌素1和下丘脑泌素2）是摄食行为、奖赏系统和睡眠/觉醒状态的关键调节剂。产生食欲素的神经元（食欲素神经元）受参与调节能量稳态和睡眠/觉醒状态的各种因素调节。蛙皮素受体亚型3（BRS 3）是一种孤儿受体，可能与能量稳态有关，在下丘脑中高度表达。然而，BRS 3调节能量稳态的神经通路在很大程度上是未知的。我们研究了BRS 3是否参与食欲素神经元的调节。使用钙成像方法，我们发现选择性BRS 3激动剂[Ac-Phe-Trp-Ala-His-（tau Bzl）-Nip-Gly-Arg-NH 2]增加食欲素神经元的细胞内钙浓度。然而，从切片制备的细胞内记录显示，BRS 3激动剂超极化食欲素神经元。BRS 3激动剂在河豚毒素存在下使食欲素神经元去极化。此外，在GABA受体阻断剂、印防己毒素和CGP 55845的存在下，BRS 3激动剂诱导去极化和增加放电频率。此外，双标记原位杂交研究显示，Brs 3 mRNA在几乎所有的食欲素神经元和这些神经元周围的许多细胞中表达。这些结果表明，BRS 3激动剂通过GABA能输入间接抑制食欲素神经元，并直接激活食欲素神经元。通过BRS 3抑制食欲素神经元的活性可能是调节进食和睡眠/觉醒状态的重要途径。该途径可能成为治疗肥胖的新靶点。
The neuropeptides orexin A and orexin B (also known as hypocretin 1 and hypocretin 2), produced in lateral hypothalamic neurons, are critical regulators of feeding behavior, the reward system, and sleep/wake states. Orexin-producing neurons (orexin neurons) are regulated by various factors involved in regulation of energy homeostasis and sleep/wakefulness states. Bombesin receptor subtype 3 (BRS3) is an orphan receptor that might be implicated in energy homeostasis and is highly expressed in the hypothalamus. However, the neural pathway by which BRS3 regulates energy homeostasis is largely unknown. We examined whether BRS3 is involved in the regulation of orexin neurons. Using a calcium imaging method, we found that a selective BRS3 agonist [Ac-Phe-Trp-Ala-His-(tau Bzl)-Nip-Gly-Arg-NH2] increased the intracellular calcium concentration of orexin neurons. However, intracellular recordings from slice preparations revealed that the BRS3 agonist hyperpolarized orexin neurons. The BRS3 agonist depolarized orexin neuron in the presence of tetrodotoxin. Moreover, in the presence of GABA receptor blockers, picrotoxin and CGP55845, the BRS3 agonist induced depolarization and increased firing frequency. Additionally, double-label in situ hybridization study revealed that Brs3 mRNA was expressed in almost all orexin neurons and many cells around these neurons. These findings suggest that the BRS3 agonist indirectly inhibited orexin neurons through GABAergic input and directly activated orexin neurons. Inhibition of activity of orexin neurons through BRS3 might be an important pathway for regulation of feeding and sleep/wake states. This pathway might serve as a novel target for the treatment of obesity.