G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease
G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease
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DOI：
10.1073/pnas.1216830110
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发表时间：
2012-12-26
影响因子：
11.1
通讯作者：
Park, Frank
中科院分区：
文献类型：
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作者：
Kwon, Michelle;Pavlov, Tengis S.;Park, Frank
多囊肾病是影响肾脏的最常见的遗传性疾病。在多囊肾病的背景下，G蛋白被调节以促进异常上皮细胞扩张和囊变的机制仍然缺乏信息。在这项研究中，我们描述了辅助蛋白，G蛋白信号调节器1(GPSM1)，也称为G蛋白信号激活物3，在常染色体显性遗传性多囊肾病(ADPKD)的直系小鼠模型中作为囊变的调节器的功能作用。与年龄匹配的囊性Gpsm1(+/+)和Gpsm1(+/-)小鼠相比，ADPKD的PKD1(V/V)模型中完全缺失Gpsm1的小鼠表现为多囊蛋白-1亚型，表现为囊性进展加快和肾功能降低。电生理研究证实了GPSM1通过Gβ-γ亚基增加异构体多囊蛋白-1/多囊蛋白-2离子通道活性的作用。综上所述，本研究证明了GPSM1在控制ADPKD同种小鼠模型中的囊性进展动力学中的重要作用，并为治疗这种代价高昂的疾病的药物开发提供了一个治疗靶点。
Polycystic kidney diseases are the most common genetic diseases that affect the kidney. There remains a paucity of information regarding mechanisms by which G proteins are regulated in the context of polycystic kidney disease to promote abnormal epithelial cell expansion and cystogenesis. In this study, we describe a functional role for the accessory protein, G-protein signaling modulator 1 (GPSM1), also knownas activator of G-protein signaling 3, to act as a modulator of cyst progression in an orthologous mouse model of autosomal dominant polycystic kidney disease (ADPKD). A complete loss of Gpsm1in the Pkd1(V/V) mousemodel of ADPKD, which displays a hypomorphic phenotype of polycystin-1, demonstrated increased cyst progression and reduced renal function compared with age-matched cystic Gpsm1(+/+) and Gpsm1(+/-) mice. Electrophysiological studies identified a role by which GPSM1 increased heteromeric polycystin-1/polycystin-2 ion channel activity via G beta gamma subunits. In summary, the present study demonstrates an important role for GPSM1 in controlling the dynamics of cyst progression in an orthologous mouse model of ADPKD and presents a therapeutic target for drug development in the treatment of this costly disease.