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.

中文翻译：

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通过 G 蛋白偶联受体和环 AMP 信号调节多囊肾病。

常染色体显性多囊肾病 (ADPKD) 是一种与多囊肝 (PLD) 和其他肾外表现相关的全身性疾病，是终末期肾病最常见的单基因病因，也是公共卫生的主要负担。许多研究表明，G 蛋白和 cAMP 信号的改变在其发病机制中起着核心作用。对于许多其他疾病（所有批准的药物中有 35% 靶向 G 蛋白偶联受体 (GPCR) 或在 GPCR 上游或下游起作用的蛋白质），靶向 GPCR 的治疗已显示出减缓 ADPKD 进展速度的有效性。托伐普坦是一种血管加压素 V2 受体拮抗剂，是第一种被监管机构批准用于治疗快速进展的 ADPKD 的药物。长效生长抑素类似物也能有效减缓多囊肾和肝的生长速度。尽管迄今为止还没有任何治疗方法能够阻止疾病的发展或阻止疾病的发展，但这些令人鼓舞的进展表明 G 蛋白和 cAMP 信号传导是一种很有前景的研究途径，可能会导致更有效和更安全的治疗。这将需要更好地了解相关的 GPCR、G 蛋白、cAMP 效应子以及控制 cAMP 信号划分的酶和 A 激酶锚定蛋白。本综述的目的是提供一般 GPCR 信号的概述；polycystin-1 (PC1) 作为推定的非典型粘附 GPCR (aGPCR) 的功能；PC1、polycystin-2 (PC2) 和 PC1-PC2 复合物在调节钙和 cAMP 信号传导中的作用；PKD 中钙和 cAMP 信号的串扰；GPCR、腺苷酸环化酶、环核苷酸磷酸二酯酶和蛋白激酶 A 作为 ADPKD 的治疗靶点。