Membrane trafficking of renal potassium channel

描述（由申请人提供）： ROMK K+通道在皮质集合管（CCD）的钾（K+）分泌中起重要作用。ROMK通道作为K+分泌的出口通道，其密度受饲料K+摄入量的调节。K+摄入的变化通过影响网格蛋白包被的囊泡介导的通道内吞作用来改变ROMK通道的表面丰度。这些适应性变化对维持膳食K+摄入量变化过程中K+稳态具有重要意义。假性醛固酮减少症II型（PHA II）是一种常染色体显性遗传疾病，以高血压和高钾血症为特征。WNK 1和WNK 4的突变导致PHA II。WNK（with-no-lysine [K]）激酶是具有催化赖氨酸的非典型位置的丝氨酸-苏氨酸蛋白激酶。最近的研究表明，增加的ROMK的内吞作用（因此，抑制ROMK）可能有助于高钾血症的PHA II引起的WNK 1和4的突变。WNK激酶的突变如何引起ROMK的内吞尚不清楚。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。在下一个资助期，我们将研究WNK引起内吞作用的机制，以及PHA II中WNK的突变如何导致ROMK内吞作用的增加。我们将进一步研究WNKs通过膳食K+摄入调节ROMK的机制和作用。这些研究将有助于我们了解肾脏如何调节K+排泄，以满足K+摄入的平衡。 项目叙述： 肾脏通过排泄多余的钾来控制血钾水平。血钾水平异常会导致心跳不规则、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.