title: WNK1 activates large-conductance Ca2+-activated K+ channels through modulation of ERK1/2 signaling.
abstract: With no lysine (WNK) kinases are members of the serine/threonine kinase family. We previously showed that WNK4 inhibits renal large-conductance Ca(2+)-activated K(+) (BK) channel activity by enhancing its degradation through a lysosomal pathway. In this study, we investigated the effect of WNK1 on BK channel activity. In HEK293 cells stably expressing the α subunit of BK (HEK-BKα cells), siRNA-mediated knockdown of WNK1 expression significantly inhibited both BKα channel activity and open probability. Knockdown of WNK1 expression also significantly inhibited BKα protein expression and increased ERK1/2 phosphorylation, whereas overexpression of WNK1 significantly enhanced BKα expression and decreased ERK1/2 phosphorylation in a dose-dependent manner in HEK293 cells. Knockdown of ERK1/2 prevented WNK1 siRNA-mediated inhibition of BKα expression. Similarly, pretreatment of HEK-BKα cells with the lysosomal inhibitor bafilomycin A1 reversed the inhibitory effects of WNK1 siRNA on BKα expression in a dose-dependent manner. Knockdown of WNK1 expression also increased the ubiquitination of BKα channels. Notably, mice fed a high-K(+) diet for 10 days had significantly higher renal protein expression levels of BKα and WNK1 and lower levels of ERK1/2 phosphorylation compared with mice fed a normal-K(+) diet. These data suggest that WNK1 enhances BK channel function by reducing ERK1/2 signaling-mediated lysosomal degradation of the channel.
authors.affiliation: Renal Division, Department of Medicine, and Department of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine;
authors.forename: Yingli
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The Fourth Affiliated Hospital, Harbin Medical University, Heilongjiang, China; and.
authors.forename: Xiang
authors.initials: X
authors.lastname: Song
authors.affiliation: Renal Division, Department of Medicine, and.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Nephrology, The Second Affiliated Hospital, Wenzhou Medical University, Zhejiang, China;
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Nephrology, The Second Affiliated Hospital, Wenzhou Medical University, Zhejiang, China;
authors.forename: Weihui
authors.initials: W
authors.lastname: Niu
authors.affiliation: Renal Division, Department of Medicine, and Renal Section, Atlanta Veterans Affairs Medical Center, Decatur, Georgia.
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Nephrology, The Second Affiliated Hospital, Wenzhou Medical University, Zhejiang, China;
authors.forename: Dingying
authors.initials: D
authors.lastname: Gu
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Bao
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: He-Ping
authors.initials: HP
authors.lastname: Ma
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Eaton
authors.affiliation: Department of Nephrology, The Second Affiliated Hospital, Wenzhou Medical University, Zhejiang, China; hcai3@emory.edu jieqiuzhuang@hotmail.com.
authors.forename: Jieqiu
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: Renal Division, Department of Medicine, and Renal Section, Atlanta Veterans Affairs Medical Center, Decatur, Georgia Department of Physiology, Emory University School of Medicine, Atlanta, Georgia; hcai3@emory.edu jieqiuzhuang@hotmail.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000076204:WNK Lysine-Deficient Protein Kinase 1; D014882:Water-Electrolyte Balance
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C498744:Wnk1 protein, mouse
keywords: Cell and transport physiology; K channels; cell signaling