WNK4 regulates Na<sup>+</sup> transport in airways

Farfel, Zvi; Mayan, Haim; Yaacov, Yasmin; Mouallem, Meir; Shaharabany, Miriam; Pauzner, Rachel; Kerem, Eitan; Wilschanski, Michael

doi:10.1111/j.1365-2362.2005.01504.x

Cited by 20 publications

(5 citation statements)

References 35 publications

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“…In Xenopus oocytes mutant WNK4 exhibits enhanced inhibition of CFTR activity when compared to wt-WNK4 (Yang et al, 2007 ). This is in agreement with the observation that PHA-II patients with WNK4 mutations exhibit changes in epithelial potential difference and conductance that resemble mild CF, which could be explained by the ability of mutant WNK4 to suppress the the epithelial sodium channel (ENaC) or CFTR in nasal epithelia and sweat ducts of PHA-II patients (Farfel et al, 2005 ; Yang et al, 2007 ).…”

Section: Wnks Crosstalk With Syk To Regulate Cftr Traffickingsupporting

confidence: 90%

Regulatory Crosstalk by Protein Kinases on CFTR Trafficking and Activity

et al. 2016

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Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a member of the ATP binding cassette (ABC) transporter superfamily that functions as a cAMP-activated chloride ion channel in fluid-transporting epithelia. There is abundant evidence that CFTR activity (i.e., channel opening and closing) is regulated by protein kinases and phosphatases via phosphorylation and dephosphorylation. Here, we review recent evidence for the role of protein kinases in regulation of CFTR delivery to and retention in the plasma membrane. We review this information in a broader context of regulation of other transporters by protein kinases because the overall functional output of transporters involves the integrated control of both their number at the plasma membrane and their specific activity. While many details of the regulation of intracellular distribution of CFTR and other transporters remain to be elucidated, we hope that this review will motivate research providing new insights into how protein kinases control membrane transport to impact health and disease.

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Section: Wnks Crosstalk With Syk To Regulate Cftr Traffickingsupporting

confidence: 90%

Regulatory Crosstalk by Protein Kinases on CFTR Trafficking and Activity

et al. 2016

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“…There are four subtypes of WNK, WNK1-4, and the chloride binding site of the kinase domain is conserved among them, but the activities of the WNK subtypes are inhibited by different Cl − concentrations, that is, WNK1 by 60-150 mM, WNK3 by 100-150 mM and WNK4 by 0-40 mM [27,28]. WNK1 and WNK4 have been shown to regulate epithelial Na + channels [30,31], CFTR [32], NKCC1 [33] and NCC [26,34]. Based on these observations, our hypothesis is that WNK1 controls the ODAs and WNK4 controls the IDAs in the c-LAECs.…”

Section: Discussionmentioning

confidence: 99%

Ambroxol-Enhanced Frequency and Amplitude of Beating Cilia Controlled by a Voltage-Gated Ca2+ Channel, Cav1.2, via pHi Increase and [Cl−]i Decrease in the Lung Airway Epithelial Cells of Mice

Nakahari,

Suzuki,

Kawaguchi

et al. 2023

IJMS

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Ambroxol (ABX), a frequently prescribed secretolytic agent which enhances the ciliary beat frequency (CBF) and ciliary bend angle (CBA, an index of amplitude) by 30%, activates a voltage-dependent Ca2+ channel (CaV1.2) and a small transient Ca2+ release in the ciliated lung airway epithelial cells (c-LAECs) of mice. The activation of CaV1.2 alone enhanced the CBF and CBA by 20%, mediated by a pHi increasei and a [Cl−]i decrease in the c-LAECs. The increase in pHi, which was induced by the activation of the Na+-HCO3− cotransporter (NBC), enhanced the CBF (by 30%) and CBA (by 15–20%), and a decrease in [Cl−]i, which was induced by the Cl− release via anoctamine 1 (ANO1), enhanced the CBA (by 10–15%). While a Ca2+-free solution or nifedipine (an inhibitor of CaV1.2) inhibited 70% of the CBF and CBA enhancement using ABX, CaV1.2 enhanced most of the CBF and CBA increases using ABX. The activation of the CaV1.2 existing in the cilia stimulates the NBC to increase pHi and ANO1 to decrease the [Cl−]i in the c-LAECs. In conclusion, the pHi increase and the [Cl−]i decrease enhanced the CBF and CBA in the ABX-stimulated c-LAECs.

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“…The finding of a KLHL3 mutation in an infant with TTN supports the notion that WNK4 may be involved in the pathogenesis of TTN. Indeed in a previous report we have proposed that WNK4 is involved in the regulation of the activity of pulmonary ENaC [17]. Such regulation was also proposed based on studies in cell culture and whole animals [18].…”

Section: Discussionmentioning

confidence: 99%

Hypercalciuria in Familial Hyperkalemia and Hypertension with KLHL3 Mutations

Mayan

Carmon²,

Oleinikov³

et al. 2015

Nephron

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Background: Familial hyperkalemia and hypertension (FHHt) is a rare genetic disorder manifested by hyperkalemia and early hypertension. Hypercalciuria is another accompanying feature. Mutations in WNK4 and WNK1 were found initially, and recently additional mutations were found in two genes, KLHL3 and CUL3, which are components of the Ubiquitin system. It was not reported whether these latter mutations are accompanied by hypercalciuria. Methods: We compared urinary calcium excretion (UCa) in affected subjects with FHHt and KLHL3 mutations, and in their unaffected family members, and in affected subjects with FHHt and WNK4 Q565E mutation. Results: Two new families with FHHt including a total number of 23 subjects, 10 of them affected, in whom previously described mutations in KLHL3 (Q309R and R528H) were identified. Presenting features were short stature in the first family, and transient tachypnea of the newborn (TTN) in the second. Affected subjects had hypercalciuria. UCa levels in affected subjects in the two families were significantly higher than in unaffected subjects (0.608 ± 0.196 vs. 0.236 ± 0.053 mmol Ca per mmol creatinine, respectively (p < 0.0001)). Hypercalciuria in FHHt with KLHL3 mutations is less severe than that observed in FHHt with the Q565E WNK4 mutation (0.608 ± 0.196 (n = 10) mmol Ca per mmol creatinine versus 0.860 ± 0.295 (n = 29), respectively (p = 0.0168)). Conclusions: FHHt caused by KLHL3 mutations is accompanied by hypercalciuria as well as hyperkalemia and hypertension. The similar phenomena observed for FHHt caused by WNK4 mutations fits the other evidence that WNK4 mutations are activating, and the aberrant mechanism of calcium handling by the kidney in FHHt.

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WNK4 regulates Na⁺ transport in airways

Abstract: Mutant WNK4 increases Na+ transport in airways, and therefore it is regulated by wild-type WNK4. This may be caused by a regulation of ENaC or a K+ channel.

Cited by 20 publications

References 35 publications

Regulatory Crosstalk by Protein Kinases on CFTR Trafficking and Activity

Regulatory Crosstalk by Protein Kinases on CFTR Trafficking and Activity

Ambroxol-Enhanced Frequency and Amplitude of Beating Cilia Controlled by a Voltage-Gated Ca2+ Channel, Cav1.2, via pHi Increase and [Cl−]i Decrease in the Lung Airway Epithelial Cells of Mice

Hypercalciuria in Familial Hyperkalemia and Hypertension with KLHL3 Mutations

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WNK4 regulates Na+ transport in airways

Abstract: Mutant WNK4 increases Na+ transport in airways, and therefore it is regulated by wild-type WNK4. This may be caused by a regulation of ENaC or a K+ channel.

Cited by 20 publications

References 35 publications

Regulatory Crosstalk by Protein Kinases on CFTR Trafficking and Activity

Regulatory Crosstalk by Protein Kinases on CFTR Trafficking and Activity

Ambroxol-Enhanced Frequency and Amplitude of Beating Cilia Controlled by a Voltage-Gated Ca2+ Channel, Cav1.2, via pHi Increase and [Cl−]i Decrease in the Lung Airway Epithelial Cells of Mice

Hypercalciuria in Familial Hyperkalemia and Hypertension with KLHL3 Mutations

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WNK4 regulates Na⁺ transport in airways