Nedvetsky Pavel I, Tamma Grazia, Beulshausen Sven, Valenti Giovanna, Rosenthal Walter, Klussmann Enno
Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Berlin, 13125, Germany.
Handb Exp Pharmacol. 2009(190):133-57. doi: 10.1007/978-3-540-79885-9_6.
Principal cells lining renal collecting ducts control the fine-tuning of body water homeostasis by regulating water reabsorption through the water channels aquaporin-2 (AQP2), aquaporin-3 (AQP3), and aquaporin-4 (AQP4). While the localization of AQP2 is subject to regulation by arginine-vasopressin (AVP), AQP3 and AQP4 are constitutively expressed in the basolateral plasma membrane. AVP adjusts the amount of AQP2 in the plasma membrane by triggering its redistribution from intracellular vesicles into the plasma membrane. This permits water entry into the cells and water exit through AQP3 and AQP4. The translocation of AQP2 is initiated by an increase in cAMP following V2R activation through AVP. The AVP-induced rise in cAMP activates protein kinase A (PKA), which in turn phosphorylates AQP2, and thereby triggers the redistribution of AQP2. Several proteins participating in the control of cAMP-dependent AQP2 trafficking have been identified; for example, A kinase anchoring proteins (AKAPs) tethering PKA to cellular compartments; phosphodiesterases (PDEs) regulating the local cAMP level; cytoskeletal components such as F-actin and microtubules; small GTPases of the Rho family controlling cytoskeletal dynamics; motor proteins transporting AQP2-bearing vesicles to and from the plasma membrane for exocytic insertion and endocytic retrieval; SNAREs inducing membrane fusions, hsc70, a chaperone, important for endocytic retrieval. In addition, cAMP-independent mechanisms of translocation mainly involving the F-actin cytoskeleton have been uncovered. Defects of AQP2 trafficking cause diseases such as nephrogenic diabetes insipidus (NDI), a disorder characterized by a massive loss of hypoosmotic urine.This review summarizes recent data elucidating molecular mechanisms underlying the trafficking of AQP2. In particular, we focus on proteins involved in the regulation of trafficking, and physiological and pathophysiological stimuli determining the cellular localization of AQP2. The identification of proteins and protein-protein interactions may lead to the development of drugs targeting AQP2 trafficking. Such drugs may be suitable for the treatment of diseases associated with dysregulation of body water homeostasis, including NDI or cardiovascular diseases (e.g., chronic heart failure) where the AVP level is elevated, inducing excessive water retention.
肾集合管内衬的主细胞通过水通道蛋白-2（AQP2）、水通道蛋白-3（AQP3）和水通道蛋白-4（AQP4）调节水的重吸收，从而精确调控机体水平衡。虽然AQP2的定位受精氨酸加压素（AVP）调控，但AQP3和AQP4在基底外侧质膜中组成性表达。AVP通过促使AQP2从细胞内囊泡重新分布到质膜，来调节质膜中AQP2的数量。这使得水能够进入细胞，并通过AQP3和AQP4排出细胞。AQP2的转位由AVP激活V2R后cAMP增加引发。AVP诱导的cAMP升高激活蛋白激酶A（PKA），PKA进而使AQP2磷酸化，从而触发AQP2的重新分布。已鉴定出几种参与cAMP依赖性AQP2转运调控的蛋白质；例如，将PKA锚定到细胞区室的A激酶锚定蛋白（AKAPs）；调节局部cAMP水平的磷酸二酯酶（PDEs）；细胞骨架成分，如F-肌动蛋白和微管；控制细胞骨架动力学的Rho家族小GTP酶；将携带AQP2的囊泡运输到质膜进行胞吐插入和胞吞回收的运动蛋白；诱导膜融合的SNAREs、伴侣蛋白hsc70，其对胞吞回收很重要。此外，还发现了主要涉及F-肌动蛋白细胞骨架的非cAMP依赖性转位机制。AQP2转运缺陷会导致诸如肾性尿崩症（NDI）等疾病，该疾病的特征是大量低渗尿液流失。本综述总结了阐明AQP2转运分子机制的最新数据。特别是，我们关注参与转运调控的蛋白质，以及决定AQP2细胞定位的生理和病理生理刺激因素。蛋白质和蛋白质-蛋白质相互作用的鉴定可能会导致开发靶向AQP2转运的药物。此类药物可能适用于治疗与机体水平衡失调相关的疾病，包括NDI或精氨酸加压素水平升高导致水潴留过多的心血管疾病（如慢性心力衰竭）。
