WNK3 Kinase Enhances the Sodium Chloride Cotransporter Expression via an ERK 1/2 Signaling Pathway

Wang, Dexuan; Zhang, Yiqian; Han, Jin-Hua; Pan, Shufang; Xu, Ning; Xu, Feng; Zhuang, Zhizhi; Caroti, Courtney M.; Zhuang, Jieqiu; Hoover, Robert S.; Gu, Dayong; Zeng, Quan; Cai, Hui

doi:10.1159/000447717

Cited by 4 publications

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References 31 publications

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“…Such (de)phosphorylation events in CCCs often involve the ‘With No Lysine’ (WNK) Ser–Thr kinases. For example, WNK1 and WNK3 enhance NCC function by increasing its expression, whereas WNK4 inhibits NCC function [ 38 , 39 ]. Interestingly, GABAergic transmission is modulated by increased WNK1 phosphorylation, which promotes NKCC1 phosphorylation/activation and KCC2 phosphorylation/inactivation in neurons [ 36 , 40 ].…”

Section: Cation-coupled Chloride Cotransporters (Cccs): From Structure To Function and Modulationmentioning

confidence: 99%

Cation-coupled chloride cotransporters: chemical insights and disease implications

Portioli

Munevar²,

Vivo³

et al. 2021

Trends in Chemistry

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Cation-coupled chloride cotransporters (CCCs) modulate the transport of sodium and/or potassium cations coupled with chloride anions across the cell membrane. CCCs thus help regulate intracellular ionic concentration and consequent cell volume homeostasis. This has been largely exploited in the past to develop diuretic drugs that act on CCCs expressed in the kidney. However, a growing wealth of evidence has demonstrated that CCCs are also critically involved in a great variety of other pathologies, motivating most recent drug discovery programs targeting CCCs. Here, we examine the structure-function relationship of CCCs. By linking recent high-resolution cryogenic electron microscopy (cryo-EM) data with older biochemical/functional studies on CCCs, we discuss the mechanistic insights and opportunities to design selective CCC modulators to treat diverse pathologies. Cation-coupled chloride cotransporters (CCCs): from structure to function and modulationCCCs are proteins (~130 kDa) of the subfamily of solute carrier transporters (see Glossary) 12 (SLC12) that modulate transport of sodium and/or potassium cations (Na + , K + ) and chloride anions (Cl -) across the cell membrane (Figure 1A). In humans, there are seven known electroneutral CCCs: the Na + -Clcotransporter NCC, the Na + -K + -Clcotransporters NKCC1 and NKCC2, and the K + -Clcotransporters KCC1, KCC2, KCC3, and KCC4 (Figure 1B) [1]. NCC and NKCC2 are expressed predominantly in the kidney [2]. NKCC1, KCC1, KCC3, and KCC4 are expressed throughout the body. KCC2 is expressed specifically in neurons [3]. CCCs are involved in physiological processes, including salt absorption and secretion, cell volume regulation, and intracellular Clconcentration setting [1,4]. As such, CCCs are primarily implicated in blood pressure regulation, cardiovascular and brain physiopathology, and diuresis, and are also associated with hearing and tumoral diseases (Figure 1C,D). Structure-function relationshipsCCCs mainly form homodimers, although multimeric states have been described in functional assays for N(K)CCs and KCCs [5][6][7]. Monomers for each of the CCC family members are characterized by a well-conserved transmembrane (TM) domain formed by 12 TM helices, one N-glycosylated extracellular (EC) domain, and, on the cytosolic side, the amino-terminal (NT) and the large carboxy-terminal (CT) domains (Figure 1A). All SLC12-CCC members share the same TM protein fold of the leucine transporter (LeuT [8], Box 1). The EC domain is characterized by a connecting loop between TM7 and TM8 in Na + -dependent CCCs, whereas Na + -independent CCCs have a longer loop between TM5 and TM6. The NT and EC domains are variable in amino acid length, much shorter than the CT domain, and poorly conserved among the CCC members. The EC domains contain glycosylation sites, whereas the intracellular domains contain phosphorylation sites to modulate CCC function (Figure 1A) [9]. Molecular heterogeneity is also provided by multiple CCC isoforms, generated by alternative splicing and alternative promote...

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Section: Cation-coupled Chloride Cotransporters (Cccs): From Structure To Function and Modulationmentioning

confidence: 99%

Cation-coupled chloride cotransporters: chemical insights and disease implications

Portioli

Munevar²,

Vivo³

et al. 2021

Trends in Chemistry

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“…Cells were harvested and processed as previously described ( Cai et al, 2006 ; Zhuang et al, 2011 ; Wang et al, 2016 ). Briefly, protease inhibitors (1 tablet per 50 ml of solution, Roche Diagnostics GmbH, 11873580001) and sodium orthovanadate 80 μM (Sigma, s6508) are added to a RIPA lysis buffer for lysing cells transiently transfected with various DNA constructs or siRNAs.…”

Section: Methodsmentioning

confidence: 99%

“…After mixing with Laemmli buffer (Bio-Rad) and incubating at 100°C for 3 min or 42°C for 15 min, the protein samples were separated by SDS-PAGE and electrophoretically transferred to polyvinylidene difluoride (PVDF) membranes (Bio-Rad) for Western blot. The probing with specific antibodies and subsequent detection with Clarity Western ECL substrate (Bio-Rad) or Super signal (Pierce) were performed according to standard procedures as described previously ( Gagnon et al, 2006 ; Wang et al, 2016 ). The antibodies used were anti-actin (EMD Millipore, MBA1501), anti-phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204), and anti-p44/42 MAPK (ERK 1/2) (Cell Signaling Technology, 9101L/9102L), anti-phospho-SPAK (Ser373)/phospho-OSR1 (Ser325) (EMD Millipore, 07-2273), anti-t-SPAK (Santa Cruz Biotechnology, sc-517361), anti-myc-Tag (Cell Signaling Technology, #2276s), and anti-BKα (Alomone Labs, APC-021).…”

Section: Methodsmentioning

confidence: 99%

“…SPAK not only participates in the regulation of ion channels (Falin et al, 2011;Warsi et al, 2014c;Ahmed et al, 2015) but also regulates a variety of carriers, including NaCl (NCC) and Na + -K + -2Cl − (NKCC) cotransporters, KCl symporters, and Na + /H + exchangers (Delpire and Gagnon, 2006;Gagnon et al, 2006;Vitari et al, 2006;Geng et al, 2009;Gagnon and Delpire, 2010). In previous studies, we showed that multiple members of the WNK family regulate BK protein expression via the ERK1/2 pathway (Zhuang et al, 2011;Liu et al, 2015) or explored the effects of SPAK and ERK1/2 in the NCC regulation process in the WNK family (Zhou et al, 2012;Feng et al, 2015;Wang et al, 2016). Although SPAK is widely expressed in the renal tubules, the link between SPAK and BK remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Stimulatory Role of SPAK Signaling in the Regulation of Large Conductance Ca2+-Activated Potassium (BK) Channel Protein Expression in Kidney

Zhang

et al. 2020

Front. Physiol.

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SPS1-related proline/alanine-rich kinase (SPAK) plays important roles in regulating the function of numerous ion channels and transporters. With-no-lysine (WNK) kinase phosphorylates SPAK kinase to active the SPAK signaling pathway. Our previous studies indicated that WNK kinases regulate the activity of the large-conductance Ca 2+activated K + (BK) channel and its protein expression via the ERK1/2 signaling pathway. It remains largely unknown whether SPAK kinase directly modulates the BK protein expression in kidney. In this study, we investigated the effect of SPAK on renal BK protein expression in both HEK293 cells and mouse kidney. In HEK293 cells, siRNAmediated knockdown of SPAK expression significantly reduced BK protein expression and increased ERK1/2 phosphorylation, whereas overexpression of SPAK significantly enhanced BK expression and decreased ERK1/2 phosphorylation in a dose-dependent manner. Knockdown of ERK1/2 prevented SPAK siRNA-mediated inhibition of BK expression. Similarly, pretreatment of HEK293 cells with either the lysosomal inhibitor bafilomycin A1 or the proteasomal inhibitor MG132 reversed the inhibitory effects of SPAK knockdown on BK expression. We also found that there is no BK channel activity in PCs of CCD in SPAK KO mice using the isolated split-open tubule single-cell patching. In addition, we found that BK protein abundance in the kidney of SPAK knockout mice was significantly decreased and ERK1/2 phosphorylation was significantly

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WNK3 Promotes Neuronal Survival after Traumatic Brain Injury in Rats

et al. 2021

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WNK3 Kinase Enhances the Sodium Chloride Cotransporter Expression via an ERK 1/2 Signaling Pathway

Cited by 4 publications

References 31 publications

Cation-coupled chloride cotransporters: chemical insights and disease implications

Cation-coupled chloride cotransporters: chemical insights and disease implications

Stimulatory Role of SPAK Signaling in the Regulation of Large Conductance Ca2+-Activated Potassium (BK) Channel Protein Expression in Kidney

WNK3 Promotes Neuronal Survival after Traumatic Brain Injury in Rats

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