Signal Transduction Section, National Institute of Diabetes and Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Eur J Pharmacol. 2011 Jun 11;660(1):119-24. doi: 10.1016/j.ejphar.2010.10.105. Epub 2011 Jan 3.
G(s)α is a ubiquitously expressed G protein α-subunit that couples receptors to the generation of intracellular cyclic AMP. The G(s)α gene GNAS is a complex gene that undergoes genomic imprinting, an epigenetic phenomenon that leads to differential expression from the two parental alleles. G(s)α is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in a small number of tissues. Albright hereditary osteodystrophy is a monogenic obesity disorder caused by heterozygous G(s)α mutations but only when the mutations are maternally inherited. Studies in mice indicate a similar parent-of-origin effect on energy and glucose metabolism, with maternal but not paternal mutations leading to obesity, reduced sympathetic nerve activity and energy expenditure, glucose intolerance and insulin resistance, with no primary effect on food intake. These effects result from G(s)α imprinting leading to severe G(s)α deficiency in one or more regions of the central nervous system, and are associated with a specific defect in melanocortins to stimulate sympathetic nerve activity and energy expenditure.
G(s)α 是一种普遍表达的 G 蛋白 α 亚基，它将受体与细胞内环磷酸腺苷的产生偶联。G(s)α 基因 GNAS 是一个复杂的基因，它经历基因组印记，这是一种表观遗传现象，导致来自两个亲本等位基因的差异表达。G(s)α 以组织特异性的方式被印记，主要从少数组织中的母本等位基因表达。阿布莱特遗传性骨营养不良症是一种单基因肥胖症，由杂合 G(s)α 突变引起，但只有当突变是母系遗传时才会发生。在小鼠中的研究表明，能量和葡萄糖代谢存在类似的亲本来源效应，母系而非父系突变导致肥胖、交感神经活动和能量消耗减少、葡萄糖耐量受损和胰岛素抵抗，而对食物摄入没有主要影响。这些效应是由 G(s)α 印记导致中枢神经系统的一个或多个区域中严重的 G(s)α 缺乏引起的，并且与刺激交感神经活动和能量消耗的黑皮质素的特定缺陷有关。
