CPT-cGMP Is A New Ligand of Epithelial Sodium Channels.
CPT-cGMP Is A New Ligand of Epithelial Sodium Channels.
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DOI：
10.7150/ijbs.13764
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发表时间：
2016
影响因子：
9.2
通讯作者：
Liu SL
中科院分区：
文献类型：
--
作者：
Ji HL;Nie HG;Chang Y;Lian Q;Liu SL
上皮钠通道（ENaC）位于上皮细胞的顶膜，负责盐和液体的重吸收。肾脏ENaC吸收盐，从而控制血清中的盐含量。ENaC功能丧失突变导致盐消耗引起的低血压，而功能获得突变导致钠排泄受损和随后的高血压以及低钾血症。ENaC活性受到细胞内和细胞外信号的调节，包括激素、神经递质、蛋白激酶和小化合物。环核苷酸广泛参与刺激蛋白激酶A和蛋白激酶G信号通路，并且令人惊讶的是，似乎也在调节ENaC中起作用。越来越多的证据表明，cGMP类似物CPT-cGMP通过细胞外途径以剂量依赖性方式可逆地激活αβγ-ENaC活性。此外，CPT-cGMP的对氯苯硫基部分和核糖2 '-羟基对于促进该化合物打开ENaC通道是必需的。作为细胞外配体，CPT-cGMP消除了钠的自抑制，这是一种与传统的NO/cGMP/PKG信号通路平行的刺激盐重吸收的新机制。总之，ENaC可能是CPT-cGMP的药物靶点，导致盐重吸收中的肾功能障碍的治疗。
Epithelial sodium channels (ENaC) are localized at the apical membrane of the epithelium, and are responsible for salt and fluid reabsorption. Renal ENaC takes up salt, thereby controlling salt content in serum. Loss-of-function ENaC mutations lead to low blood pressure due to salt-wasting, while gain-of-function mutations cause impaired sodium excretion and subsequent hypertension as well as hypokalemia. ENaC activity is regulated by intracellular and extracellular signals, including hormones, neurotransmitters, protein kinases, and small compounds. Cyclic nucleotides are broadly involved in stimulating protein kinase A and protein kinase G signaling pathways, and, surprisingly, also appear to have a role in regulating ENaC. Increasing evidence suggests that the cGMP analog, CPT-cGMP, activates αβγ-ENaC activity reversibly through an extracellular pathway in a dose-dependent manner. Furthermore, the parachlorophenylthio moiety and ribose 2'-hydroxy group of CPT-cGMP are essential for facilitating the opening of ENaC channels by this compound. Serving as an extracellular ligand, CPT-cGMP eliminates sodium self-inhibition, which is a novel mechanism for stimulating salt reabsorption in parallel to the traditional NO/cGMP/PKG signal pathway. In conclusion, ENaC may be a druggable target for CPT-cGMP, leading to treatments for kidney malfunctions in salt reabsorption.