Pissios Pavlos, Trombly Daniel J, Tzameli Iphigenia, Maratos-Flier Eleftheria
Section on Obesity, Research Division, Joslin Diabetes Center, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Endocrinology. 2003 Aug;144(8):3514-23. doi: 10.1210/en.2002-0004.
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.
黑色素浓缩激素（MCH）是一种下丘脑神经肽，在能量平衡中起关键作用。与许多神经肽一样，它通过两种G蛋白偶联受体发出信号。MCH受体1（MCHR1）是在啮齿动物中表达的唯一受体，与G(i)和G(q)蛋白偶联。关于MCH及其受体所涉及的细胞内途径知之甚少。利用稳定表达MCHR1的HEK293细胞，我们证明MCH通过MCHR1发挥作用，拮抗福斯可林（一种增加细胞内cAMP水平的腺苷酸环化酶激活剂）的作用。MCH还抑制G(s)偶联的β-肾上腺素能受体诱导的cAMP生成。在HEK293细胞中，激活G(i)或G(s)依赖性途径通常会导致ERK磷酸化。与对cAMP合成的相反作用不同，同时用MCH和福斯可林处理会导致ERK的协同激活。这种协同作用通过百日咳毒素非依赖性途径进行，并且需要几种酶活性，如蛋白激酶A、蛋白激酶C、磷脂酶C和Src激酶。最后，我们提供证据表明这种正向相互作用不仅限于细胞系，在大脑中也可以观察到。
