Melanin-concentrating hormone depresses L-, N-, and P/Q-type voltage-dependent calcium channels in rat lateral hypothalamic neurons
Melanin-concentrating hormone depresses L-, N-, and P/Q-type voltage-dependent calcium channels in rat lateral hypothalamic neurons
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DOI：
10.1113/jphysiol.2002.019372
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发表时间：
2002-07-01
影响因子：
5.5
通讯作者：
van den Pol, AN
中科院分区：
文献类型：
--
作者：
Gao, XB;van den Pol, AN
黑色素浓缩激素（melanin - concentration hormone， MCH）是一种由19个氨基酸组成的环状肽，仅由下丘脑外侧区（LH）的神经元合成。它与许多大脑功能有关，最近由于其在能量稳态中的作用而引起了人们的兴趣。MCH轴突和受体遍布整个大脑。先前的报道为利用转染MCH受体基因的非神经元细胞了解MCH的细胞作用奠定了基础；这些细胞对MCH的反应表现出细胞质钙的增加，表明多肽具有兴奋作用。在本研究中，我们对117个来自LH培养和脑切片的神经元进行了全细胞记录，以检查MCH的作用。MCH降低了几乎所有被测神经元中电压依赖性钙电流的振幅。在-80 mV ~ 0 mV的脉冲范围内，抑制作用呈剂量依赖性（IC50 = 7.8 nM）。GTPgammaS对g蛋白的先验激活完全消除了低MCH浓度下的MCH诱导效应，降低了高MCH浓度下的MCH诱导效应。百日咳毒素（PTX）抑制g蛋白可阻断高浓度MCH诱导的抑制作用。在大多数神经元中，脉冲前去极化导致mch诱导的钙电流抑制的衰减。这些数据表明，在LH神经元中，MCH通过ptx敏感的G蛋白通路(可能是G（i)/G(o)通路）对钙电流产生抑制作用。LH神经元中存在L-型、N-型和P/ q型钙通道，其中L-型和N型通道占电压激活电流的大部分（各占40%左右）；MCH对三种电流均有减弱作用（平均抑制50%），其中对n型电流的抑制作用最大。与之前关于非神经元细胞的数据显示mhc引起的钙增加相反，我们的数据表明，在LH神经元中发生相反的情况。钙电流的衰减与神经元中肽的抑制作用是一致的。
Melanin-concentrating hormone (MCH), a cyclic 19-amino-acid peptide, is synthesized exclusively by neurons in the lateral hypothalamic (LH) area. It is involved in a number of brain functions and recently has raised interest because of its role in energy homeostasis. MCH axons and receptors are found throughout the brain. Previous reports set the foundation for understanding the cellular actions of MCH by using non-neuronal cells transfected with the MCH receptor gene; these cells exhibited an increase in cytoplasmic calcium in response to MCH, suggesting an excitatory action for the peptide. In the study presented here, we have used whole-cell recording in 117 neurons from LH cultures and brain slices to examine the actions of MCH. MCH decreased the amplitude of voltage-dependent calcium currents in almost all tested neurons. The inhibition desensitized rapidly (18 s to half maximum at 100 nM concentration) and was dose-dependent (IC50 = 7.8 nM) when activated with a pulse from -80 mV to 0 mV. A priori activation of G-proteins with GTPgammaS completely eliminated the MCH-induced effect at low MCH concentrations and reduced the MCH-induced effect at high MCH concentrations. Inhibition of G-proteins with pertussis toxin (PTX) blocked the MCH-induced inhibitory effect at high MCH concentrations. Pre-pulse depolarization resulted in an attenuation of the MCH-induced inhibition of calcium currents in most neurons. These data suggest that MCH exerts an inhibitory effect on calcium currents via PTX-sensitive G-protein pathways, probably the G(i)/G(o) pathway, in LH neurons. L-, N- and P/Q-type calcium channels were identified in LH neurons, with L- and N-type channels accounting for most of the voltage-activated current (about 40% each); MCH attenuated each of the three types (mean 50% depression), with the greatest inhibition found for N-type currents. In contrast to previous data on non-neuronal cells showing an MHC-evoked increase in calcium, our data suggest that the reverse occurs in LH neurons. The attenuation of calcium currents is consistent with an inhibitory action for the peptide in neurons.