THE HUMEN PERSPECTIVE幻灯片.pptVIP

THE HUMEN PERSPECTIVE Disorders Associated with G protein-Coupled Receptors 基本原理 cAMP途径概念 细胞外信号与相应的受体结合，导致细胞内第二信使cAMP的水平变化而引起细胞反应的信号通路。 途径总揽 激素→G蛋白耦联受体→G蛋白→腺苷酸环化酶→cAMP→依赖cAMP的蛋白激酶A→基因调控蛋白→基因转录 cAMP信号途径 Gs调节模型 Gs与Rs相互作用，激活腺苷酸环化酶，提高cAMP水平。 Gi调节模型 Gi与Ri相互作用，抑制腺苷酸环化酶，降低cAMP水平。 G蛋白概述 腺苷酸环化酶 蛋白激酶A 环腺苷酸磷酸二酯酶 Gs调节模型 Gi调节模型 先天性肾源性尿崩症（CNDI） 致病原因 额外功能的获得：细胞无限增生 额外功能的获得：细胞无限增生 致病原因 正常的甲状腺细胞只有在与垂体TSH（促甲状腺激素）应答时才分泌甲状腺素，而这些甲状腺瘤的细胞不用与垂体激素TSH应答就能大量分泌甲状腺素。这些细胞中的TSH受体蛋白的一个氨基酸被替代了，从而影响了蛋白质第三个胞内环的结构。这一突变使TSH受体蛋白连续不断的刺激位于它内表面的G蛋白，通过这一途径连续的释放信号，这不但会导致甲状腺素的过量分泌，同时还会导致细胞的过量增殖从而导致肿瘤。 Somatic mutation  genetic mutation 基因突变与G蛋白构象改变 * * 文字版 图文版 The human genome may encode as many as 2000 different GPCRs. Their importance in human biology is reflected by the fact that more than one-quarter of all prescription drugs act as ligands that bind to this huge superfamily of receptors. A number of inherited disorders have been traced to defects in both GPCRs and heterotrimeric G protein . Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disease in which infants suffer serious dehydration as the result of an inability of their kidneys to produce a concentrated urine. If not diagnosed promptly, the chronic dehydration can produce mental retardation, inadequate growth, and even death. The disorder results from the inability of the cells of the kidneys to respond to the hormone vasopressin (antidiuretic hormone). As noted on page 153, some case of this disease result from mutations in aquaporins, The water channels of the plasma membrane. In most case ,however, the fault lies in the vasopressin receptor, which is typically shortened as the result of a mutation that introduces a stop codon into the mRNA, causing premature termination of polypeptide synthesis (page 484). A different type of debilitating mutation in this same GPCR leads to an amino acid substitution at the junction between the third transmembrane segment and the second intracellular loop (site 4, figu