CFTR is required for PKA-regulated ATP sensitivity of Kir1.1 potassium channels in mouse kidney

Lu, Ming; Li, Qiang; Egan, Marie E.; Caplan, Michael J.; Boulpaep, Emile L.; Giebisch, Gerhard; Hebert, Steven C.

doi:10.1172/jci26961

Cited by 63 publications

(53 citation statements)

References 72 publications

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“…The association of ROMK with NHERFs serves to bring ROMK into closer proximity to the cystic fibrosis transmembrane regulator protein (CFTR) (32). This ROMK-CFTR interaction is in turn required for the native ATP and glybenclamide sensitivity of apical K 1 channels in the TAL (33). Impaired CFTR-dependent regulation of ROMK in the TAL may potentially explain the propensity for hypochloremic alkalosis and "pseudo-Bartter's syndrome" in patients with cystic fibrosis (33,34).…”

Section: Anatomy and Morphologymentioning

confidence: 99%

Thick Ascending Limb of the Loop of Henle

Mount

2014

Clinical Journal of the American Society of Nephrology

141

106

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The thick ascending limb occupies a central anatomic and functional position in human renal physiology, with critical roles in the defense of the extracellular fluid volume, the urinary concentrating mechanism, calcium and magnesium homeostasis, bicarbonate and ammonium homeostasis, and urinary protein composition. The last decade has witnessed tremendous progress in the understanding of the molecular physiology and pathophysiology of this nephron segment. These advances are the subject of this review, with emphasis on particularly recent developments.

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Section: Anatomy and Morphologymentioning

confidence: 99%

Thick Ascending Limb of the Loop of Henle

Mount

2014

Clinical Journal of the American Society of Nephrology

141

106

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“…The cystic fibrosis transmembrane conductance regulator (CFTR) protein is highly expressed in many segments of the mammalian nephron (1)(2)(3), where it can function in these homeostatic processes as a regulator of other transport proteins (4,5). We (6)(7)(8) and others (9) have identified CFTR as an important regulator of the 30 pS inward rectifier potassium channel ROMK (Kir1.1) that mediates potassium secretion by distal nephron segments (10). The expression of CFTR in apical plasma membranes is required for the gating of ROMK by cytosolic ATP, providing a link between cell metabolism and potassium secretory activity (8,9).…”

mentioning

confidence: 99%

“…We (6)(7)(8) and others (9) have identified CFTR as an important regulator of the 30 pS inward rectifier potassium channel ROMK (Kir1.1) that mediates potassium secretion by distal nephron segments (10). The expression of CFTR in apical plasma membranes is required for the gating of ROMK by cytosolic ATP, providing a link between cell metabolism and potassium secretory activity (8,9). Accordingly, the sensitivity of ROMK to ATP is lost in CFTR knockout and CFTR-ΔF508 transgenic mice (8).…”

mentioning

confidence: 99%

“…The expression of CFTR in apical plasma membranes is required for the gating of ROMK by cytosolic ATP, providing a link between cell metabolism and potassium secretory activity (8,9). Accordingly, the sensitivity of ROMK to ATP is lost in CFTR knockout and CFTR-ΔF508 transgenic mice (8). Interaction of ROMK with CFTR is also required for partial inhibition of ROMK channel activity by the sulfonylurea compound glibenclamide (6)(7)(8).…”

mentioning

confidence: 99%

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Mouse cystic fibrosis transmembrane conductance regulator forms cAMP-PKA–regulated apical chloride channels in cortical collecting duct

Lu¹,

Dong²,

Egan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in many segments of the mammalian nephron, where it may interact with and modulate the activity of a variety of apical membrane proteins, including the renal outer medullary potassium (ROMK) K + channel. However, the expression of CFTR in apical cell membranes or its function as a Cl − channel in native renal epithelia has not been demonstrated. Here, we establish that CFTR forms protein kinase A (PKA)-activated Cl − channels in the apical membrane of principal cells from the cortical collecting duct obtained from mice. These Cl − channels were observed in cell-attached apical patches of principal cells after stimulation by forskolin/3-isobutyl-1-methylxanthine. Quiescent Cl − channels were present in patches excised from untreated tubules because they could be activated after exposure to Mg-ATP and the catalytic subunit of PKA. The single-channel conductance, kinetics, and anion selectivity of these Cl − channels were the same as those of recombinant mouse CFTR channels expressed in Xenopus laevis oocytes. The CFTR-specific closed-channel blocker CFTR inh -172 abolished apical Cl − channel activity in excised patches. Moreover, apical Cl − channel activity was completely absent in principal cells from transgenic mice expressing the ΔF508 CFTR mutation but was present and unaltered in ROMK-null mice. We discuss the physiologic implications of open CFTR Cl − channels on salt handling by the collecting duct and on the functional CFTR–ROMK interactions in modulating the metabolic ATP-sensing of ROMK.

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“…However, CF patients have no significant abnormality in renal function (106). CFTR functionally regulates ENaC (57,94) and ROMK (51,62,85), which are also regulated by WNK4. How much the enhanced inhibition of CFTR by WNK4 FHH affects ENaC and ROMK, and to what extent the overall effect contributes to the pathogenesis of FHH, are questions to be addressed in future studies.…”

Section: Wnk4 Regulates Ion Transporters and Channels In The Transcelmentioning

confidence: 99%

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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CFTR is required for PKA-regulated ATP sensitivity of Kir1.1 potassium channels in mouse kidney

Cited by 63 publications

References 72 publications

Thick Ascending Limb of the Loop of Henle

Thick Ascending Limb of the Loop of Henle

Mouse cystic fibrosis transmembrane conductance regulator forms cAMP-PKA–regulated apical chloride channels in cortical collecting duct

WNK4-mediated regulation of renal ion transport proteins

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