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Regulation of CFTR Bicarbonate Channel Activity by WNK1: Implications for Pancreatitis and CFTR-Related Disorders

Authors
 Yonjung Kim  ;  Ikhyun Jun  ;  Dong Hoon Shin  ;  Jihoon G Yoon  ;  He Piao  ;  Jinsei Jung  ;  Hyun Woo Park  ;  Mary Hongying Cheng  ;  Ivet Bahar  ;  David C Whitcomb  ;  Min Goo Lee 
Citation
 CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, Vol.9(1) : 79-103, 2020-01 
Journal Title
 CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY 
Issue Date
2020-01
Keywords
Bicarbonate Secretion ; Epithelia ; Ion Selectivity ; Pancreatitis
Abstract
Backgraoud & aims: Aberrant epithelial bicarbonate (HCO3-) secretion caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is associated with several diseases including cystic fibrosis and pancreatitis. Dynamically regulated ion channel activity and anion selectivity of CFTR by kinases sensitive to intracellular chloride concentration ([Cl-]i) play an important role in epithelial HCO3- secretion. However, the molecular mechanisms of how [Cl-]i-dependent mechanisms regulate CFTR are unknown. Methods: We examined the mechanisms of the CFTR HCO3- channel regulation by [Cl-]i-sensitive kinases using an integrated electrophysiological, molecular, and computational approach including whole-cell, outside-out, and inside-out patch clamp recordings and molecular dissection of WNK1 and CFTR proteins. In addition, we analyzed the effects of pancreatitis-causing CFTR mutations on the WNK1-mediated regulation of CFTR. Results: Among the WNK1, SPAK, and OSR1 kinases that constitute a [Cl-]i-sensitive kinase cascade, the expression of WNK1 alone was sufficient to increase the CFTR bicarbonate permeability (PHCO3/PCl) and conductance (GHCO3) in patch clamp recordings. Molecular dissection of the WNK1 domains revealed that the WNK1 kinase domain is responsible for CFTR PHCO3/PCl regulation by direct association with CFTR, while the surrounding N-terminal regions mediate the [Cl-]i-sensitivity of WNK1. Furthermore, the pancreatitis-causing R74Q and R75Q mutations in the elbow helix 1 of CFTR hampered WNK1-CFTR physical associations and reduced WNK1-mediated CFTR PHCO3/PCl regulation. Conclusion: The CFTR HCO3- channel activity is regulated by [Cl-]i and a WNK1-dependent mechanism. Our results provide new insights into the regulation of the ion selectivity of CFTR and the pathogenesis of CFTR-related disorders.
Files in This Item:
T202001105.pdf Download
DOI
10.1016/j.jcmgh.2019.09.003
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Yon Jung(김연정) ORCID logo https://orcid.org/0000-0003-0251-8711
Piao He(박학) ORCID logo https://orcid.org/0000-0002-1817-3167
Shin, Dong Hoon(신동훈)
Yoon, Jihoon G.(윤지훈) ORCID logo https://orcid.org/0000-0002-4401-7803
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Jun, Ik Hyun(전익현) ORCID logo https://orcid.org/0000-0002-2160-1679
Jung, Jinsei(정진세) ORCID logo https://orcid.org/0000-0003-1906-6969
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175986
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