Membrane trafficking of renal potassium channel

描述(由申请人提供)： ROMK K+通道在大脑皮层集合管(CCDs)的基础钾(K+)分泌中起重要作用。作为K+分泌的出口通道，CCDs中ROMK通道的密度受膳食K+摄入量的调节。K+摄入的变化通过影响笼蛋白包裹的囊泡介导的通道内吞作用来改变ROMK通道的表面丰度。这些适应性变化对于在饮食K+摄入量变化期间维持K+动态平衡非常重要。假性醛固酮减少症II型(PHA II)是一种常染色体显性遗传病，以高血压和高钾血症为特征。WNK1和WNK4的突变导致PHA II。WNK(无赖氨酸[K])激酶是一种具有非典型催化赖氨酸位置的丝氨酸-苏氨酸蛋白激酶。最近的研究表明，ROMK的内吞作用增加(从而抑制ROMK)可能是WNK1和4突变导致的PHA II高钾血症的原因之一。WNK激酶的突变如何导致ROMK的内吞作用尚不清楚。本研究的长期目标是研究ROMK通道膜转运的分子机制及其在肾脏生理和疾病中的重要性。在下一个资助阶段，我们将研究WNKS导致内吞作用的机制，以及WNKS在PHA II中的突变如何导致ROMK内吞作用增加。我们将进一步研究WNKS在饮食K+摄入调节ROMK中的机制和作用。这些研究将帮助我们了解肾脏如何调节K+排泄，以满足K+摄取的平衡。 项目说明： 肾脏通过排泄过量的钾，在控制血钾水平中起着至关重要的作用。血钾水平异常会导致心跳不齐、肌肉无力和猝死。我们的研究旨在了解肾脏在生理和疾病状态下是如何排泄钾的。

DESCRIPTION (provided by applicant): ROMK K+ channels play essential roles in the baseline potassium (K+) secretion in cortical collecting ducts (CCDs). As exit pathways for K+ secretion, the density of ROMK channels in CCDs is regulated by dietary K+ intake. Variations of K+ intake alter surface abundance of ROMK channels by affecting clathrin-coated vesicle- mediated endocytosis of channels. These adaptive changes are important for maintaining K+ homeostasis during variations of dietary K+ intake. Pseudohypoaldosteronism type II (PHA II) is an autosomal-dominant disease characterized by hypertension and hyperkalemia. Mutations of WNK1 and WNK4 cause PHA II. WNK (with-no-lysine [K]) kinases are serine-threonine protein kinases with an atypical placement of the catalytic lysine. Recent studies suggest that increased endocytosis of ROMK (thus, inhibition of ROMK) may contribute to hyperkalemia in PHA II caused by mutations of WNK1 and 4. How mutations of WNK kinases cause endocytosis of ROMK is not known. The long-term goal of our research is to study the molecular mechanism for membrane trafficking of ROMK channel and its importance in renal physiology and diseases. For the next funding period, we will study the mechanism by which WNKs cause endocytosis and how mutations of WNKs in PHA II lead to increased endocytosis of ROMK. We will further examine the mechanism and role of WNKs in the regulation of ROMK by dietary K+ intake. These studies will help us understand how kidney adjusts K+ excretion to meet the balance of K+ intake. Project Narrative: Kidney plays an essential role in the control of blood potassium level by excreting excess potassium. Abnormality in blood potassium level causes irregular heart beat, muscle weakness, and sudden death. Our studies aim to understand how kidney excretes potassium in physiological and diseased states.