Parks Gregory S, Olivas Nicholas D, Ikrar Taruna, Sanathara Nayna M, Wang Lien, Wang Zhiwei, Civelli Olivier, Xu Xiangmin
Department of Pharmacology, University of California Irvine, Irvine, CA, 92697, USA Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, 92697, USA.
Department of Anatomy and Neurobiology, University of California Irvine, Irvine, CA, 92697, USA.
J Physiol. 2014 May 15;592(10):2183-96. doi: 10.1113/jphysiol.2013.268771. Epub 2014 Mar 17.
Melanin-concentrating hormone (MCH)-producing neurons are known to regulate a wide variety of physiological functions such as feeding, metabolism, anxiety and depression, and reward. Recent studies have revealed that MCH neurons receive projections from several wake-promoting brain regions and are integral to the regulation of rapid eye movement (REM) sleep. Here, we provide evidence in both rats and mice that MCH neurons express histamine-3 receptors (H3R), but not histamine-1 (H1R) or histamine-2 (H2R) receptors. Electrophysiological recordings in brain slices from a novel line of transgenic mice that specifically express the reporter ZsGreen in MCH neurons show that histamine strongly inhibits MCH neurons, an effect which is TTX insensitive, and blocked by the intracellular presence of GDP-β-S. A specific H3R agonist, α-methylhistamine, mimicks the inhibitory effects of histamine, and a specific neutral H3R antagonist, VUF 5681, blocks this effect. Tertiapin Q (TPQ), a G protein-dependent inwardly rectifying potassium (GIRK) channel inhibitor, abolishes histaminergic inhibition of MCH neurons. These results indicate that histamine directly inhibits MCH neurons through H3R by activating GIRK channels and suggest that that inhibition of the MCH system by wake-active histaminergic neurons may be responsible for silencing MCH neurons during wakefulness and thus may be directly involved in the regulation of sleep and arousal.
已知产生黑色素浓缩激素（MCH）的神经元可调节多种生理功能，如进食、新陈代谢、焦虑抑郁以及奖赏。最近的研究表明，MCH神经元接收来自多个促进觉醒的脑区的投射，并且是快速眼动（REM）睡眠调节不可或缺的一部分。在此，我们在大鼠和小鼠中均提供了证据，证明MCH神经元表达组胺3受体（H3R），但不表达组胺1（H1R）或组胺2（H2R）受体。在一个新的转基因小鼠品系的脑片中进行电生理记录，该品系在MCH神经元中特异性表达报告基因ZsGreen，结果显示组胺强烈抑制MCH神经元，这种效应不依赖于河豚毒素（TTX），并且被细胞内存在的GDP-β-S所阻断。一种特异性H3R激动剂α-甲基组胺模拟了组胺的抑制作用，而一种特异性中性H3R拮抗剂VUF 5681阻断了这种效应。G蛋白依赖性内向整流钾（GIRK）通道抑制剂特替阿平Q（TPQ）消除了组胺对MCH神经元的抑制作用。这些结果表明，组胺通过激活GIRK通道直接通过H3R抑制MCH神经元，并提示觉醒活跃的组胺能神经元对MCH系统的抑制可能是导致MCH神经元在清醒时沉默的原因，因此可能直接参与睡眠和觉醒的调节。
