Dept. of Physiology & Pharmacology,Oregon Health & Science University, Portland, OR 97239-3098, USA.
Am J Physiol Endocrinol Metab. 2012 Jun 1;302(11):E1399-406. doi: 10.1152/ajpendo.00565.2011. Epub 2012 Mar 20.
Hypothalamic proopiomelanocortin (POMC) neurons are controlled by many central signals, including serotonin. Serotonin increases POMC activity and reduces feeding behavior via serotonion [5-hydroxytryptamine (5-HT)] receptors by modulating K(+) currents. A potential K(+) current is the M-current, a noninactivating, subthreshold outward K(+) current. Previously, we found that M-current activity was highly reduced in fasted vs. fed states in neuropeptide Y neurons. Because POMC neurons also respond to energy states, we hypothesized that fasting may alter the M-current and/or its modulation by serotonergic input to POMC neurons. Using visualized-patch recording in neurons from fed male enhanced green fluorescent protein-POMC transgenic mice, we established that POMC neurons expressed a robust M-current (102.1 ± 6.7 pA) that was antagonized by the selective KCNQ channel blocker XE-991 (40 μM). However, the XE-991-sensitive current in POMC neurons did not differ between fed and fasted states. To determine if serotonin suppresses the M-current via the 5-HT(2C) receptor, we examined the effects of the 5-HT(2A)/5-HT(2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) on the M-current. Indeed, DOI attenuated the M-current by 34.5 ± 6.9% and 42.0 ± 5.3% in POMC neurons from fed and fasted male mice, respectively. In addition, the 5-HT(1B)/5-HT(2C) receptor agonist m-chlorophenylpiperazine attenuated the M-current by 42.4 ± 5.4% in POMC neurons from fed male mice. Moreover, the selective 5-HT(2C) receptor antagonist RS-102221 abrogated the actions of DOI in suppressing the M-current. Collectively, these data suggest that although M-current expression does not differ between fed and fasted states in POMC neurons, serotonin inhibits the M-current via activation of 5-HT(2C) receptors to increase POMC neuronal excitability and, subsequently, reduce food intake.
下丘脑的前阿黑皮素原（POMC）神经元受许多中枢信号的控制，包括血清素。血清素通过调节钾电流来增加 POMC 的活性并减少摄食行为。一种潜在的钾电流是 M 电流，一种非失活的、阈下外向钾电流。先前，我们发现与进食状态相比，禁食状态下神经肽 Y 神经元中的 M 电流活性显著降低。因为 POMC 神经元也对能量状态有反应，所以我们假设禁食可能会改变 M 电流及其通过血清素能输入对 POMC 神经元的调制。使用来自喂食雄性增强型绿色荧光蛋白-POMC 转基因小鼠的神经元中的可视化贴片记录，我们确定 POMC 神经元表达了一种强大的 M 电流（102.1 ± 6.7 pA），该电流被选择性的 KCNQ 通道阻滞剂 XE-991（40 μM）所拮抗。然而，在喂食和禁食状态之间，POMC 神经元中的 XE-991 敏感电流没有差异。为了确定血清素是否通过 5-HT2C 受体抑制 M 电流，我们检查了 5-HT2A/5-HT2C 受体激动剂 2,5-二甲氧基-4-碘苯丙胺（DOI）对 M 电流的影响。事实上，DOI 分别使喂食和禁食雄性小鼠的 POMC 神经元中的 M 电流降低了 34.5 ± 6.9%和 42.0 ± 5.3%。此外，5-HT1B/5-HT2C 受体激动剂 m-氯苯哌嗪使喂食雄性小鼠的 POMC 神经元中的 M 电流降低了 42.4 ± 5.4%。此外，选择性 5-HT2C 受体拮抗剂 RS-102221 阻断了 DOI 抑制 M 电流的作用。总之，这些数据表明，尽管在 POMC 神经元中，M 电流的表达在进食和禁食状态之间没有差异，但血清素通过激活 5-HT2C 受体抑制 M 电流，增加 POMC 神经元的兴奋性，进而减少食物摄入。
