Receptor guanylyl cyclases (GCs) are single membrane spanning, multidomain enzymes, that synthesize cGMP in response to natriuretic peptides or other ligands. They are evolutionarily conserved from sea urchins to humans and regulate diverse physiologies. Most family members are phosphorylated on 4 to 7 conserved serines or threonines at the beginning of their kinase homology domains. This review describes studies that demonstrate that phosphorylation and dephosphorylation are required for activation and inactivation of these enzymes, respectively. Phosphorylation sites in GC-A, GC-B, GC-E, and sea urchin receptors are discussed, as are mutant receptors that mimic the dephosphorylated inactive or phosphorylated active forms of GC-A and GC-B, respectively. A salt bridge model is described that explains why phosphorylation is required for enzyme activation. Potential kinases, phosphatases, and ATP regulation of GC receptors are also discussed. Critically, knock-in mice with glutamate substitutions for receptor phosphorylation sites are described. The inability of opposing signaling pathways to inhibit cGMP synthesis in mice where GC-A or GC-B cannot be dephosphorylated demonstrates the necessity of receptor dephosphorylation in vivo. Cardiac hypertrophy, oocyte meiosis, long-bone growth/achondroplasia, and bone density are regulated by GC phosphorylation, but additional processes are likely to be identified in the future.

中文翻译：

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鸟苷酸环化酶 (GC)-A 和其他膜 GC 受体的磷酸化依赖性调节。


受体鸟苷酸环化酶 (GC) 是单跨膜多域酶，可响应利尿钠肽或其他配体合成 cGMP。从海胆到人类，它们在进化上是保守的，并调节不同的生理机能。大多数家族成员在其激酶同源结构域起始处的 4 至 7 个保守丝氨酸或苏氨酸上被磷酸化。这篇综述描述了证明这些酶的激活和失活分别需要磷酸化和去磷酸化的研究。讨论了 GC-A、GC-B、GC-E 和海胆受体中的磷酸化位点，以及分别模拟 GC-A 和 GC-B 去磷酸化非活性或磷酸化活性形式的突变受体。描述了盐桥模型，解释了为什么酶激活需要磷酸化。还讨论了 GC 受体的潜在激酶、磷酸酶和 ATP 调节。重要的是，描述了用谷氨酸取代受体磷酸化位点的敲入小鼠。在 GC-A 或 GC-B 不能去磷酸化的小鼠中，相反的信号通路无法抑制 cGMP 合成，这表明体内受体去磷酸化的必要性。心脏肥大、卵母细胞减数分裂、长骨生长/软骨发育不全和骨密度均受 GC 磷酸化的调节，但未来可能会发现其他过程。