Melanin-concentrating hormone receptor 1 activates extracellular signal-regulated kinase and synergizes with Gs-coupled pathways
Melanin-concentrating hormone receptor 1 activates extracellular signal-regulated kinase and synergizes with Gs-coupled pathways
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DOI：
10.1210/en.2002-0004
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发表时间：
2003-08-01
期刊：
影响因子：
4.8
通讯作者：
Maratos-Flier, E
中科院分区：
文献类型：
--
作者：
Pissios, P;Trombly, DJ;Maratos-Flier, E
黑色素浓缩激素(MCH)是下丘脑的一种神经肽，在能量平衡中起关键作用。像许多神经肽一样，它通过两个G蛋白偶联受体发出信号。MCH受体1(MCHR1)是唯一表达于啮齿动物及其对G(I)和G(Q)蛋白的受体。对MCH及其受体参与的细胞内通路知之甚少。利用稳定表达MCHR1的HEK293细胞，我们证明了MCH通过MCHR1发挥作用，拮抗腺苷环化酶激活剂Forsklin的作用，后者可以增加细胞内cAMP水平。MCH还抑制G(S)偶联的β-肾上腺素能受体对cAMP的诱导。激活G(I)或G(S)依赖的通路通常会导致HEK293细胞中ERK的磷酸化。与cAMP合成相反，MCH和Forsklin同时处理导致ERK的协同激活。这种协同作用是通过百日咳毒素不依赖的途径进行的，需要几种酶活性，如蛋白激酶A、蛋白激酶C、磷脂酶C和Src激酶。最后，我们提供的证据表明，这种积极的相互作用不仅限于细胞系，而且在大脑中也可以观察到。
Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that plays a key role in energy homeostasis. Like many neuropeptides, it signals through two G protein-coupled receptors. MCH receptor 1 (MCHR1) is the sole receptor expressed in rodents and couples to G(i) and G(q) proteins. Little is known about the intracellular pathways engaged by MCH and its receptor. Using HEK293 cells stably expressing MCHR1, we demonstrate that MCH, acting through MCHR1, antagonizes the action of forskolin, an adenylate cyclase activator that increases intracellular levels of cAMP. MCH also inhibits cAMP induction by the G(s)-coupled beta-adrenergic receptor. Activation of either the G(i)- or G(s)-dependent pathway typically results in ERK phosphorylation in HEK293 cells. In contrast to opposing actions on cAMP synthesis, simultaneous MCH and forskolin treatment results in synergistic activation of ERK. This synergy proceeds through pertussis toxin-independent pathways and requires several enzymatic activities such as protein kinase A, protein kinase C, phospholipase C, and Src kinase. Finally, we provide evidence that such positive interactions are not limited to cell lines but can also be observed in the brain.