Molecular mechanism of the NKCC transporter

摘要 钠-钾-氯-共转运体(NKCC)家族转运蛋白对药物的重吸收起关键作用 肾脏和身体其他部位的离子。作为较大的溶质载体12(SLC12A)家族的成员， 这些转运蛋白将钠、钾和氯转移到细胞膜上，以保持离子。 动态平衡和调节血压。由于它们在生理学中的重要作用，它们也 是医学上最广泛的靶向转运蛋白之一。药物，如环状利尿剂和噻嗪 利尿剂已经使用了几十年，是治疗以下疾病的基本药物 浮肿、肝硬变、心力衰竭和高血压。然而，尽管它们被广泛使用，人们对它们的了解却很少 它们运作的分子机制。这个项目将通过研究 从基础、基础科学的角度看NKCC运输机集团。一项体外功能测试将是 开发的目的是为了在明确的系统中研究NKCC的传输机制。关键组件 负责离子识别和结合以及抑制剂结合的位置将使用 诱变与功能分析相结合。以上知识将与结构学相结合 关于NKCC的特征，以了解其功能。作为一个整体，这项研究将揭示 关于NKCC运输商如何运作以及它们如何成为目标的机制。这些信息将导致 更好的药品，副作用更少。

Abstract The sodium-potassium-chloride-cotransporter (NKCC) family of transporters are critical to the reabsorption of ions in the kidney and other parts of the body. As a member of the larger solute carrier 12 (SLC12A) family, these transporters move sodium, potassium, and chloride across the cell membrane in order to maintain ionic homeostasis and regulate blood pressure. As a result of their important roles in physiology, they are also among the most widely targeted transporters in medicine. Drugs such as the loop diuretics and thiazide diuretics have been in use for decades, and are fundamental medications to treating conditions such as edema, cirrhosis, heart failure, and hypertension. Yet despite their widespread use, little is known about the molecular mechanism by which they operate. This project will address that gap in knowledge, by studying the NKCC group of transporters from a fundamental, basic science perspective. An in vitro functional assay will be developed in order to study the transport mechanism of NKCC in a well-defined system. Key components responsible for ion recognition and binding, as well as inhibitor binding sites will be determined using mutagenesis coupled with functional assays. The above knowledge will be combined with structural characterizations about NKCC to understand its function. As a whole, this study will reveal the fundamental mechanisms about how NKCC transporters operate and how they are targeted. This information will lead to better pharmaceuticals, with fewer side effects.