THE HUMEN THE HUMENPERSPECTIVE —— Disorders Associated with G protein-Coupled Receptors Karp P631 焦义（ ） 2005 年 12 月

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.

人类基因组能够编码多达 2000 中不同的 G 蛋 白偶联受体（ GPCRs ）。大约有 1/4 的处方药 品是作为与这类受体超家族中的某一受体的配 基而发挥作用的，由此可以看出 G 蛋白受体的 重要性。 相当一部分遗传性紊乱都可以上溯到 GPCRs 和异三聚 G 蛋白的缺陷。

What is G protein? What is G protein?What is G protein?What is G protein? What is GPCR? What is GPCR?What is GPCR?What is GPCR? Signal transduction. Signal transduction.Signal transduction.Signal transduction. Diseases associated with G Diseases associated with GDiseases associated with GDiseases associated with G protein and GPCR. protein and GPCR.

Heterotrimeric G-proteins were discovered and characterized by Martine Rodbell and his colleagues at the National Institutes in the early 1970s.These proteins are referred to as G proteins because they bind guanine nucleotides,either GDP or GTP Heterotrimeric G-proteins were discovered and characterized by Martine Rodbell and his colleagues at the National Institutes in the early 1970s.These proteins are referred to as G proteins because they bind guanine nucleotides,either GDP or GTP 1 、 Discovery Alfred G. Gilman University of Texas Southwestern Medical Center at Dallas Dallas, TX, USA born 1941 Martin Rodbell National Institute of Environmental Health Sciences Research Triangle Park, NC, USA Born 1925, died 1998

2 、 Structure “ 大 G” ：由 αβγ 三个 亚基组成 Gα 能与 GTP 或 GDP 结合，有内在的 GTP 酶活性，起 “ 分子开关 作用 ” Two switch domains have been identified, that change position when GTP substitutes for GDP on G a.

2 、 Structure 三聚体 GTP 结合调节蛋白，简称 G 蛋白，位于质 膜内胞浆一侧，由 α βγ 三个亚基构成。 Βγ 二聚 体通过共价结合锚于膜上起稳定 α 亚基的作用，而 α 亚基本身具有 GTP 酶活性，能催化所结合的 ATP 水 解，恢复无活性的三聚体状态。 G 蛋白在信号转导过 程中起着分子开关的作用。当 α 亚基与 GDP 结合时 处于关闭状态，与 GTP 结合时处与开启状态。 back

1.structure The G-protein coupled receptor (GPCR) family transduces extracellular signals across the plasma membrane They consist of seven transmembrane helices that are connected by loops. The N-terminal extremity is always located on the extracellular side while the C-terminus extends into the cytoplasm.

右图为 G 蛋白耦联型 受体该受体为 7 次跨膜 蛋白，胞外结构域识 别胞外信号分子并与 之结合，胞内结构域 与 G 蛋白耦联。通过 与 G 蛋白耦联，调节 相关酶活性，在细胞 内产生第二信使，从 而将胞外信号跨膜传 递到胞内。 图示的八个位点为突 变位置，这些突变会 导致一系列的不正常 现象。 1.structure back

Signal transduction Signal transduction Signal transduction by GPCR 1. Signal transduction by GPCR When a hormone or neurotransmitter binds to a GPCR, it induces a change in conformation in the extracellular ligand-binding site. This change in conformation is transferred across the plasma membrane and causes a change in the cytoplasmic loops of the receptor which, in turn,leads to an increase in the affinity of the receptor for a G protein,they forms a receptor-G protein complex. When a hormone or neurotransmitter binds to a GPCR, it induces a change in conformation in the extracellular ligand-binding site. This change in conformation is transferred across the plasma membrane and causes a change in the cytoplasmic loops of the receptor which, in turn,leads to an increase in the affinity of the receptor for a G protein,they forms a receptor-G protein complex.

Then interaction with the receptor induces a conformational change in the alpha subunit,causing the release of GDP, which is followed by binding of GTP. While in the activated state, a single receptor can activate a number of G protein molecules, providing a means of signal amplification.

GPCRs are activated by a wide variety of ligands, including neurotransmitters, hormones, growth factors, odorant molecules and light, and are encoded by the largest gene family in most animal,and GPCR have many activating pathway. GPCRs are activated by a wide variety of ligands, including neurotransmitters, hormones, growth factors, odorant molecules and light, and are encoded by the largest gene family in most animal,and GPCR have many activating pathway.

2.cAMP signal transduction pathway

G-protein coupled receptors (GPCRs) are one of the largest gene families of signaling proteins. Residing in the plasma membrane with seven transmembrane domains, GPCRs respond to extracellular stimuli that include catecholamine neurotransmitters, neuropeptides, larger protein hormones, lipids, nucleotides and other biological molecules. When a GPCR binds its extracellular ligand, it interacts with a G-protein to transduce a signal across the membrane into the cellular interior.

G-proteins are a heterotrimeric complex containing a Ga subunit with GTPase activity, as well as b and g subunits. Ga can exist in an active state and an inactive state. Ga in the off state has GDP bound and does not activate downstream signaling molecules. When a GPCR is activated by ligand, it stimulates Ga subunits to bind GTP instead of GDP and become active, dissociating from the receptor and from the b/g subunits to activate downstream signaling factors like the enzyme adenylyl cyclase that synthesizes cyclic-AMP (cAMP) from ATP. Ga turns itself back off again with its intrinsic GTPase activity, hydrolyzing GTP to GDP to become inactive again. back

Diseases Defective G Protein Albright’s hereditary osteodystrophy and pseudohypoparathyroidisms Gs α McCune-Albright syndrome Gs α Pituitary,thyroid tumors Gs α Adrenocortical,ovarian tumors Gi α Combined precocious puberty and peudohypoparathyroidism Gs α Human Diseases Linked to the G Protein Pathway

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