Dopamine recruits D1A receptors to Na-K-ATPase-rich caveolar plasma membranes in rat renal proximal tubules.
Dopamine recruits D1A receptors to Na-K-ATPase-rich caveolar plasma membranes in rat renal proximal tubules.
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多巴胺将 D1A 受体募集到大鼠肾近曲小管中富含 Na-K-ATP 酶的细胞膜穴质膜上。
DOI：
10.1152/ajprenal.00023.2004
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Lokhandwala,MustafaF
中科院分区：
文献类型：
--
作者：
Trivedi,Meghna;Narkar,VihangA;Hussain,Tahir;Lokhandwala,MustafaF
肾近端小管多巴胺D1A受体的激活导致钠转运体(Na-K-ATPase和Na/H交换器)的抑制，导致钠重吸收的减少。D1a受体除了定位于细胞膜外，在基础条件下主要存在于细胞内的隔室。我们用[~3H]SCH-23390结合和免疫印迹法观察到，多巴胺在大鼠肾近端小管上向质膜募集D1A受体。此外，使用药物调节剂的放射配基结合和/或免疫印迹实验表明，多巴胺诱导的D1A受体募集需要激活细胞表面的D1样受体，激活腺苷环化酶，以及具有内部酸性的完整的内吞囊泡。这项研究的一个关键发现是，这些被招募的D1A受体是有功能的，因为它们增强了多巴胺诱导的[35S]GTPγS结合、cAMP积累和Na-K-ATPase抑制。有趣的是，多巴胺增加了D1A受体的免疫反应性，特别是在蔗糖密度梯度分离的富含小窝蛋白的质膜上。为了支持这一观察结果，免疫共沉淀研究表明，D1A受体与小窝蛋白-2以激动剂依赖的方式相互作用。富含小窝蛋白的质膜含有较高含量的Na-K-α酶1亚单位，它是近端小管D1A受体信号转导的下游靶点。这些结果表明，多巴胺通过D1样受体-腺苷环化酶途径将D1A受体招募到质膜上。这些新招募的受体与G蛋白偶联，增加cAMP，并参与多巴胺介导的近端小管Na-K-ATPase的抑制。此外，多巴胺诱导的D1A受体重新聚集到富含小窝蛋白的质膜上，使它们与SD大鼠近端小管上的Na-K-ATPase等靶点非常接近。
Activation of dopamine D1Areceptors in renal proximal tubules causes inhibition of sodium transporters (Na-K-ATPase and Na/H exchanger), leading to a decrease in sodium reabsorption. In addition to being localized on the plasma membrane, D1Areceptors are mainly present in intracellular compartments under basal conditions. We observed, using [3H]SCH-23390 binding and immunoblotting, that dopamine recruits D1Areceptors to the plasma membrane in rat renal proximal tubules. Furthermore, radioligand binding and/or immunoblotting experiments using pharmacological modulators showed that dopamine-induced D1Areceptor recruitment requires activation of cell surface D1-like receptors, activation of adenylyl cyclase, and intact endocytic vesicles with internal acidic pH. A key finding of this study was that these recruited D1Areceptors were functional because they potentiated dopamine-induced [35S]GTPγS binding, cAMP accumulation, and Na-K-ATPase inhibition. Interestingly, dopamine increased immunoreactivity of D1Areceptors specifically in caveolin-rich plasma membranes isolated by a sucrose density gradient. In support of this observation, coimmunoprecipitation studies showed that D1Areceptors interacted with caveolin-2 in an agonist-dependent fashion. The caveolin-rich plasma membranes had a high content of the α1-subunit of Na-K-ATPase, which is a downstream target of D1Areceptor signaling in proximal tubules. These results show that dopamine, via the D1-like receptor-adenylyl cyclase pathway, recruits D1Areceptors to the plasma membrane. These newly recruited receptors couple to G proteins, increase cAMP, and participate in dopamine-mediated inhibition of Na-K-ATPase in proximal tubules. Moreover, dopamine-induced recruitment of D1Areceptors to the caveolin-rich plasma membranes brings them in close proximity to targets such as Na-K-ATPase in proximal tubules of Sprague-Dawley rats.
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