Comparative molecular biology of the natriuretic peptide system (Molecular dissection and mechanism of differentiation of chloride cells)

我们使用比较的方法，通过使用具有形态和功能特化的动物，如可以在淡水和海水中生存的鳗鱼，以及可以在pH 3.5的湖泊中生存和生长的Osorezan dace，来深入了解体液动态平衡的复杂调节系统。(1)通过对配体和相应受体的分析，我们发现钠尿肽(NP)系统是控制鳗鱼常盐度的关键内分泌系统。NP不仅参与转运到不同盐度时对各种原有转运蛋白的快速调节，还能刺激皮质醇和生长激素的分泌，从而参与长期适应。我们还从不同的脊椎动物物种中发现了具有独特渗透调节功能的NPs，如鲨鱼和八角鳗，以评估NP家族的分子进化。(2)通过鉴定DACE从中性水转移到酸性水时高诱导的离子转运体、通道及其相关分子，阐明了Osorezan dace酸适应的分子机制。此外，与耐酸有关的分子主要在氯离子细胞中表达。(3)硬骨鱼的渗透调节在很大程度上是通过被称为氯化物细胞的特殊细胞主动的盐分运输实现的。氯离子细胞富含Na，K-ATPase，反映了其非凡的离子转运能力。利用氯细胞的这一独特性质，我们成功地鉴定了一个可能与Na，K-ATPase功能偶联的K通道；鉴定这种K通道一直是动物生理学中的一个长期目标。(4)鳗鱼NP受体的放射自显影定位显示其在鳃软骨细胞中的分布异常密集，提示NP系统与骨代谢密切相关，为骨研究开辟了一条新的途径。

We used the comparative approach to gain insights into the complex regulatory system of the body fluid homeostasis by using animals with morphological and functional specializations such as the eel that can survive both in freshwater and seawater and the Osorezan dace that can live and grow in a pH 3.5 lake. (1) Through the analyses of both ligands and the corresponding receptors, we showed that the natriuretic peptide (NP) system is a key endocrine system that governs the euryhalinity of eel. NP is not only involved in quick regulation of various pre-existing transporters upon transfer to different salinities, but also stimulates secretion of cortisol and growth hormone, thereby being involved in long-term adaptation. We also identified NPs from diverse vertebrate species that perform unique osmoregulation such as sharks and hagfish to assess molecular evolution of the NP family. (2) Molecular mechanism of acid adaptation of the Osorezan dace was clarified by identifying ion transporters, channel, and their related molecules that become highly induced when dace are transferred from neutral to acidic water. Furthermore, the molecules responsible for the acid tolerance were mainly expressed in chloride cells. (3) Osmoregulation in teleost fish is achieved largely through active salt transport by specialized cells known as chloride cells. Reflecting their extraordinary power of ion transport, chloride cells are rich in Na, K-ATPase. Exploiting this unique property of the chloride cell, we succeeded in identifying a K channel likely to be functionally coupled with Na, K-ATPase ; identification of such a K channel has been a long-standing goal in animal physiology. (4) Autoradiographic localization of eel NP receptor revealed an unexpectedly dense localization in the gill chondrocytes, suggesting tight relationship between the NP system and bone metabolism, which then open a new avenue in the field of bone research.