Mutations in the melanocortin-4 receptor (MC4R) in humans are the single most common cause of rare monogenic 1severe obesity, and polymorphisms in this gene are also associated with obesity in the general population. The MC4R is a G-protein coupled receptor, and in vitro analysis suggests that MC4R can signal through several different G-protein subtypes. In vivo studies show complex outcomes, with different G-proteins in different cells responsible for different physiological responses linked to obesity. There is an emerging consensus that Gαq-linked signals in the paraventricular nucleus of the hypothalamus are essential for normal satiety and the control of feeding behavior. Many MC4R mutations have been analyzed for the molecular defect underlying their association with obesity, which has revealed a group - referred to as class V mutants - with no measurable change in receptor function. However, Gαq-linked signaling leading to Ca2+ release has only been examined for a few MC4R mutations. In this study, we have examined seven MC4R class V mutants, as well as two other well-characterized signal-defective mutants as controls, with respect to G-protein signaling coupled to cAMP production, mitogen-activated protein kinase (MAPK) activation, and Ca2+ release. These data confirm, with one exception (E308K), the expected pattern of cAMP and MAPK signaling for wild type and mutant MC4R. Our results also demonstrate normal MSH-induced Ca2+ signals for wild type as well as all the class V mutants, but not the signal-defective controls. Thus, the means by which class V MC4R mutations lead to obesity remains an open question.

中文翻译：

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选定的肥胖相关的melanocortin-4受体V类突变体的信号通路分析。

人类中黑皮质素4受体（MC4R）的突变是罕见的单基因1重性肥胖的最常见原因，并且该基因的多态性也与普通人群的肥胖有关。MC4R是一种G蛋白偶联受体，体外分析表明MC4R可以通过几种不同的G蛋白亚型发出信号。体内研究显示出复杂的结果，不同细胞中的不同G蛋白负责与肥胖有关的不同生理反应。越来越多的共识认为，下丘脑室旁核中的Gαq连锁信号对于正常的饱腹感和控制进食行为至关重要。已经分析了许多MC4R突变与肥胖相关的分子缺陷，它揭示了一个称为V类突变体的组，其受体功能没有可测量的变化。但是，仅针对少数MC4R突变检查了导致Ca2 +释放的Gαq连锁信号。在这项研究中，我们检查了7个MC4R V类突变体，以及另外两个表征良好的信号缺陷突变体作为对照，研究了与cAMP产生，促分裂原激活的蛋白激酶（MAPK）激活相关的G蛋白信号传导，和Ca2 +释放。这些数据确认了一个例外（E308K），即野生型和突变型MC4R的cAMP和MAPK信号转导的预期模式。我们的结果还证明了正常的MSH诱导的野生型以及所有V类突变体的Ca2 +信号，但不是信号缺陷对照。因此，V类MC4R突变导致肥胖的方法仍然是一个悬而未决的问题。