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Modulation of polycystic kidney disease by G-protein coupled receptors and cyclic AMP signaling

机译：G蛋白偶联受体和循环AMP信号传导的多囊肾疾病调制

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disorder associated with polycystic liver disease (PLD) and other extrarenal manifestations, the most common monogenic cause of end-stage kidney disease, and a major burden for public health. Many studies have shown that alterations in G-protein and cAMP signaling play a central role in its pathogenesis. As for many other diseases (35% of all approved drugs target G-protein coupled receptors (GPCRs) or proteins functioning upstream or downstream from GPCRs), treatments targeting GPCR have shown effectiveness in slowing the rate of progression of ADPKD. Tolvaptan, a vasopressin V2 receptor antagonist is the first drug approved by regulatory agencies to treat rapidly progressive ADPKD. Long-acting somatostatin analogs have also been effective in slowing the rates of growth of polycystic kidneys and liver. Although no treatment has so far been able to prevent the development or stop the progression of the disease, these encouraging advances point to G-protein and cAMP signaling as a promising avenue of investigation that may lead to more effective and safe treatments. This will require a better understanding of the relevant GPCRs, G-proteins, cAMP effectors, and of the enzymes and A-kinase anchoring proteins controlling the compartmentalization of cAMP signaling. The purpose of this review is to provide an overview of general GPCR signaling; the function of polycystin-1 (PC1) as a putative atypical adhesion GPCR (aGPCR); the roles of PC1, polycystin-2 (PC2) and the PC1-PC2 complex in the regulation of calcium and cAMP signaling; the cross-talk of calcium and cAMP signaling in PKD; and GPCRs, adenylyl cyclases, cyclic nucleotide phosphodiesterases, and protein kinase A as therapeutic targets in ADPKD.
机译：常染色体占优势性多囊肾疾病（ADPKD）是与多囊肝病（PLD）和其他突出表现有关的全身疾病，最常见的肾病的最常见的单一的原因，以及公共卫生的主要负担。许多研究表明，G蛋白和阵营信号传导的改变在其发病机制中起着核心作用。至于许多其他疾病（35％的所有批准的药物靶向G蛋白偶联受体（GPCR）或功能上游或下游的蛋白质），靶向GPCR的治疗表明，在减缓ADPKD的进展速率方面表现出有效性。罗瓦膜，血压素V2受体拮抗剂是监管机构批准的第一批治疗迅速逐步的ADPKD的药物。长效的生长抑素类似物也有效地减缓了多囊肾脏和肝的生长速度。虽然到目前为止，但到目前为止没有治疗能够防止发育或停止疾病的进展，但这些令人振奋的推动指向G-蛋白和营地信令作为可能导致更有效和安全的治疗的有希望的调查大道。这将需要更好地理解相关的GPCR，G-蛋白，营地效应，以及控制CAMP信号传导的舱室化的酶和A-kinase锚定蛋白。本综述的目的是提供一般GPCR信令的概述;多孔-1（PC1）作为推定的非典型粘附GPCR（AGPCR）的功能; PC1，多囊蛋白-2（PC2）和PC1-PC2复合物在钙和阵营信号调节中的作用; PKD中钙和营信噪比信号的串扰;和GPCRS，腺苷酸环酶，环状核苷酸磷酸二酯酶和蛋白激酶A作为ADPKD的治疗靶标。

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  • 来源
    《Cellular Signalling》 |2020年第2020期|共25页
  • 作者

    Sussman Caroline R.; Wang Xiaofang; Chebib Fouad T.; Torres Vicente E.;

  • 作者单位

    Mayo Clin Div Nephrol &

    Hypertens 200 First St SW Rochester MN 55905 USA;

    Mayo Clin Div Nephrol &

    Hypertens 200 First St SW Rochester MN 55905 USA;

    Mayo Clin Div Nephrol &

    Hypertens 200 First St SW Rochester MN 55905 USA;

    Mayo Clin Div Nephrol &

    Hypertens 200 First St SW Rochester MN 55905 USA;

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  • 正文语种 eng
  • 中图分类 细胞形态学;
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