Regulation of aquaporin-2 trafficking.
Regulation of aquaporin-2 trafficking.
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DOI：
10.1007/978-3-540-79885-9_6
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发表时间：
2009-01-01
影响因子：
--
通讯作者：
Klussmann, Enno
中科院分区：
文献类型：
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作者：
Nedvetsky, Pavel I;Tamma, Grazia;Klussmann, Enno
肾集合管内衬的主要细胞通过水通道水通道蛋白-2（AQP 2）、水通道蛋白-3（AQP 3）和水通道蛋白-4（AQP 4）调节水重吸收来控制身体水稳态的微调。AQP 2的定位受精氨酸加压素（AVP）的调节，而AQP 3和AQP 4组成型表达于基底外侧质膜。AVP通过触发AQP 2从细胞内囊泡重新分布到质膜中来调节质膜中AQP 2的量。这允许水进入细胞并通过AQP 3和AQP 4排出。AQP 2的转位是由AVP激活V2 R后cAMP增加启动的。AVP诱导的cAMP升高激活蛋白激酶A（PKA），进而磷酸化AQP 2，从而触发AQP 2的再分布。已经鉴定了参与控制cAMP依赖性AQP 2运输的几种蛋白质;例如，将PKA拴系到细胞区室的A激酶锚定蛋白（AKAP）;调节局部cAMP水平的磷酸二酯酶（PDE）;细胞骨架组分如F-肌动蛋白和微管;控制细胞骨架动力学的Rho家族的小GTP酶;马达蛋白质运输AQP 2轴承囊泡进出质膜外吞插入和内吞检索; SNARE诱导膜融合，hsc 70，伴侣，内吞检索的重要。此外，已发现主要涉及F-肌动蛋白细胞骨架的不依赖cAMP的易位机制。AQP 2运输缺陷导致的疾病，如肾源性尿崩症（NDI），一种疾病的特点是大量的低渗尿的损失。特别是，我们专注于蛋白质参与调节贩运，生理和病理生理刺激决定细胞定位的AQP 2。蛋白质和蛋白质-蛋白质相互作用的鉴定可能导致靶向AQP 2运输的药物的开发。这样的药物可适用于治疗与身体水分稳态失调相关的疾病，包括NDI或心血管疾病（例如，慢性心力衰竭），其中AVP水平升高，诱导过度水潴留。
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.