WNK1 and WNK4 modulate CFTR activity

Yang, Chao; Liu, Xuehong; Paliege, Alex; Zhu, Xiaoman; Bachmann, S.; Dawson, David C.; Ellison, David H.

doi:10.1016/j.bbrc.2006.11.151

Cited by 51 publications

(55 citation statements)

References 19 publications

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“…On the other hand, nothing is known about the mechanisms that stabilize the physiologically important resting state, which is vital for the efficiency and fidelity of any physiological process. We reasoned that a potential pathway that stabilizes the resting state is the WNK/SPAK pathway, since WNK1 and WNK4 were reported to affect the activity of Slc26a6 (25) and CFTR expressed in Xenopus oocytes (27) and mammalian cells (26). To determine the role of the WNK and SPAK kinases in vivo, we used the approach of gene silencing by siRNA in sealed ducts in primary culture (28), which proved very efficient in these ducts (21,29).…”

Section: Role Of the Wnk And Spak Kinases In Vivomentioning

confidence: 99%

“…Therefore, in the next stage we used the tools in Figure 4G to ask whether the WNK/SPAK kinases act on CFTR and whether IRBIT/PP1 antagonizes the effect of the WNKs on CFTR expression and activity. CFTR and the SLC26 transporters were reported to be inhibited by the WNKs (25,27). However, a recent study reported that at low cytoplasmic Cl -, WNK1 phosphorylates SPAK, which then increases CFTR HCO 3 -permeability and inhibits the SLC26 transporters and CFTR-dependent HCO 3 -transport (26).…”

Section: The Wnk and Spak Kinases Pp1 And Irbit In Regulation Of Cftrmentioning

confidence: 99%

“…Here, we asked what mechanism stabilizes the resting or inhibited state of the pancreatic and parotid ducts and examined the relationship between the events that inhibit secretion and IRBIT. We focused on the WNK kinases, since it was reported that they inhibit Slc26a6 (25,26) and CFTR (27), although a recent study reported that WNK1 changes the HCO 3 -permeability of CFTR rather than inhibiting its activity (26). How the WNKs regulate the SLC26 transporters and CFTR is not known.…”

Section: Introductionmentioning

confidence: 99%

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IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

Yang¹,

Li²,

So³

et al. 2011

J. Clin. Invest.

102

172

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Section: Role Of the Wnk And Spak Kinases In Vivomentioning

confidence: 99%

Section: The Wnk and Spak Kinases Pp1 And Irbit In Regulation Of Cftrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

Yang¹,

Li²,

So³

et al. 2011

J. Clin. Invest.

102

172

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“…WNK4 was shown to be well colocalized with CFTR in the colon (39). More recently, Yang et al (117) reported that CFTR is inhibited by both WNK1 and WNK4. The effect of WNK4 on CFTR is similar to that on ROMK (117).…”

Section: Wnk4 Regulates Ion Transporters and Channels In The Transcelmentioning

confidence: 96%

WNK4-mediated regulation of renal ion transport proteins

Peng

Warnock²

2007

American Journal of Physiology-Renal Physiology

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Peng J-B, Warnock DG. WNK4-mediated regulation of renal ion transport proteins. Am J Physiol Renal Physiol 293: F961-F973, 2007. First published July 18, 2007; doi:10.1152/ajprenal.00192.2007], a serine-threonine kinase that is expressed in the distal nephron of the kidney, are linked to familial hyperkalemic hypertension (FHH). The imbalanced electrolyte homeostasis in FHH has led to studies toward an understanding of WNK4-mediated regulation of ion transport proteins in the kidney. A growing number of ion transport proteins for Na, and Cl Ϫ , including ion channels and transporters in the transcellular pathway and claudins in the paracellular pathway, are shown to be regulated by WNK4 from studies using models ranging from Xenopus laevis oocytes to transgenic and knockin mice. WNK4 regulates these transport proteins in different directions and by different cellular mechanisms. The common theme of WNK4-mediated regulation is to alter the abundance of ion transport proteins at the plasma membrane, with the exception of claudins, which are phosphorylated in the presence of WNK4. The regulation of WNK4 can be blocked by the full-length WNK1, whose action is in turn antagonized by a kidney-specific WNK1 variant lacking the kinase domain. In addition, WNK4 also activates stress-related serine-threonine kinases to regulate members of the SLC12 family members of cation-chloride cotransporters. In many cases, the FHH-causing mutants of WNK4 exhibit differences from wild-type WNK4 in regulating ion transport proteins. These regulations well explain the clinical features of FHH and provide insights into the multilayered regulation of ion transport processes in the distal nephron. WNK1; kidney; hypertension; ion channel; transporter THE DISTAL PORTION OF THE nephron, including the distal convoluted tubule (DCT), the connecting tubule (CNT), and the cortical collecting duct (CCT), is important for Na ϩ , K ϩ , and Ca 2ϩ homeostasis (65,80). An array of ion transport proteins located in this portion of the nephron plays important roles in maintaining an electrolyte balance and, in turn, a normal blood pressure. The roles of these ion transport proteins in maintaining a normal blood pressure have been demonstrated in genetic disorders (59,103). For examples, gain-of-function in the amiloride-sensitive epithelial Na ϩ channel (ENaC) causes hypertension in Liddle's syndrome (32, 90); loss-of-function in the thiazide-sensitive Na ϩ -Cl Ϫ cotransporter (NCC; SLC12A3; also known as TSC or NCCT) results in hypotension in Gitelman syndrome (91).The linkage of familial hyperkalemic hypertension (FHH; also known as pseudohypoaldosteronism type II, PHAII, or Gordon's syndrome) (30), an autosomal dominant form of hypertension, to two members of the WNK [With No K (lysine)] family of protein serine-threonine kinases has powered efforts to understand the roles of WNK kinases in regulating ion transporters in the distal tubule (104). The WNK family consists of four members; they all lack an invariant lysine residue in the catalytic site ...

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“…Although attractive, the model does not yet explain how increased concentration of HCO 3 2 would associate with fluid transport, and it cannot account for the fact that proximal small ducts are the richest sites of CFTR/AQP/carbonic anhydrase expression. Also, other studies show that WNKs inhibit CFTR (Yang et al 2007(Yang et al , 2011. No doubt this exciting field of volume-sensitive kinases may not only be of relevance to kidney and blood pressure regulation, but also to salt and water transport in other epithelia.…”

Section: Cftr and Anion Exchangermentioning

confidence: 97%

The Cystic Fibrosis of Exocrine Pancreas

Wilschanski

Novak

2013

Cold Spring Harbor Perspectives in Medicine

125

113

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The cystic fibrosis transmembrane conductance regulator (CFTR) protein is highly expressed in the pancreatic duct epithelia and permits anions and water to enter the ductal lumen. This results in an increased volume of alkaline fluid allowing the highly concentrated proteins secreted by the acinar cells to remain in a soluble state. This work will expound on the pathophysiology and pathology caused by the malfunctioning CFTR protein with special reference to ion transport and acid-base abnormalities both in humans and animal models. We will also discuss the relationship between cystic fibrosis (CF) and pancreatitis, and outline present and potential therapeutic approaches in CF treatment relevant to the pancreas.

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WNK1 and WNK4 modulate CFTR activity

Cited by 51 publications

References 19 publications

IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

WNK4-mediated regulation of renal ion transport proteins

The Cystic Fibrosis of Exocrine Pancreas

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