Levine M A
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Arch Med Res. 1999 Nov-Dec;30(6):522-31. doi: 10.1016/s0188-4409(99)00075-2.
Signal-transducing guanine nucleotide-binding proteins (G proteins) couple extracellular receptor proteins to intracellular effector enzymes and ion channels, and therefore are critical mediators of cellular responses to external stimuli. G proteins are comprised of three subunits (alpha, beta, gamma), each encoded by many different genes. The multiplicity of G protein subunits facilitates great combinatorial variability, which, in part, accounts for the ability of G proteins to interact with many different receptor and effector proteins. Hundreds of G protein-coupled receptors have been identified, and their unique patterns of expression among a restricted number of cell types contributes greatly to the apparent specificity of hormone action. Mutations that either activate or inactivate some of these receptors account for a number of highly specific syndromes, which affect a limited number of target tissues. By contrast, most G proteins are widely expressed in many tissues. Accordingly, mutations in these signaling molecules would be expected to produce a more generalized pattern of hormone dysfunction. Activating mutations in the gene (GNAS1) that encode the alpha subunit of the G protein that stimulates adenylyl cyclase (AC) have been identified in many endocrine neoplasms and diverse tissues of patients with McCune-Albright syndrome. The McCune-Albright syndrome is characterized by autonomous endocrine function, hyperpigmented skin lesions, and fibrous dysplasia of bone--effects which reflect the ability of CAMP to stimulate cell function and proliferation in a wide variety of tissues. The unusual features of the McCune-Albright syndrome are explained by the mosaic distribution of cells bearing the mutant allele, an observation that is most consistent with postzygotic mutation of GNAS1. Experimental analysis of this syndrome has extended our understanding of the clinical and biochemical consequences of dysfunctional G protein action and has provided a bench-to-bedside demonstration of the critical role that G proteins play in transmembrane signal transduction in humans.
信号转导鸟嘌呤核苷酸结合蛋白（G蛋白）将细胞外受体蛋白与细胞内效应酶和离子通道偶联，因此是细胞对外部刺激作出反应的关键介质。G蛋白由三个亚基（α、β、γ）组成，每个亚基由许多不同的基因编码。G蛋白亚基的多样性促进了巨大的组合变异性，这在一定程度上解释了G蛋白与许多不同受体和效应蛋白相互作用的能力。已经鉴定出数百种G蛋白偶联受体，它们在有限数量的细胞类型中的独特表达模式极大地促成了激素作用的明显特异性。激活或失活其中一些受体的突变导致了许多高度特异性的综合征，这些综合征影响有限数量的靶组织。相比之下，大多数G蛋白在许多组织中广泛表达。因此，预计这些信号分子中的突变会产生更普遍的激素功能障碍模式。在许多内分泌肿瘤以及McCune-Albright综合征患者的各种组织中，已发现编码刺激腺苷酸环化酶（AC）的G蛋白α亚基的基因（GNAS1）存在激活突变。McCune-Albright综合征的特征是自主内分泌功能、色素沉着过度的皮肤病变和骨纤维发育不良，这些效应反映了环磷酸腺苷（CAMP）在多种组织中刺激细胞功能和增殖的能力。McCune-Albright综合征的异常特征可以通过携带突变等位基因的细胞的镶嵌分布来解释，这一观察结果与GNAS1的合子后突变最为一致。对该综合征的实验分析扩展了我们对功能失调的G蛋白作用的临床和生化后果的理解，并提供了从 bench 到 bedside 的证据，证明了G蛋白在人类跨膜信号转导中所起的关键作用。
