Molecular Diversity and Regulation of Renal Potassium Channels

Hebert, Steven C.; Desir, Gary V.; Giebisch, Gerhard; Wang, Wenhui

doi:10.1152/physrev.00051.2003

Cited by 290 publications

(309 citation statements)

References 644 publications

(721 reference statements)

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“…ROMK K ϩ channels present on the apical membrane of the distal renal tubules are important for baseline renal K ϩ secretion (20)(21)(22)(23). Another type of K ϩ channels, maxi-K, are also present in the distal renal tubules and important for K ϩ secretion in response to increase in tubular fluid flow (23,24).…”

mentioning

confidence: 99%

Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms

Lazrak

Liu

Huang³

2006

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

161

207

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WNK kinases are serine-threonine kinases with an atypical placement of the catalytic lysine. Intronic deletions with increased expression of a ubiquitous long WNK1 transcript cause pseudohypoaldosteronism type 2 (PHA II), characterized by hypertension and hyperkalemia. Here, we report that long WNK1 inhibited ROMK1 by stimulating its endocytosis. Inhibition of ROMK by long WNK1 was synergistic with, but not dependent on, WNK4. A smaller transcript of WNK1 lacking the N-terminal 1-437 amino acids is expressed highly in the kidney. Whether expression of the KS-WNK1 (kidney-specific, KS) is altered in PHA II is not known. We found that KS-WNK1 did not inhibit ROMK1 but reversed the inhibition of ROMK1 caused by long WNK1. Consistent with the lack of inhibition by KS-WNK1, we found that amino acids 1-491 of the long WNK1 were sufficient for inhibiting ROMK. Dietary K ؉ restriction decreases ROMK abundance in the renal cortical-collecting ducts by stimulating endocytosis, an adaptative response important for conservation of K ؉ during K ؉ deficiency. We found that K ؉ restriction in rats increased whole-kidney transcript of long WNK1 while decreasing that of KS-WNK1. Thus, KS-WNK1 is a physiological antagonist of long WNK1. Hyperkalemia in PHA II patients with PHA II mutations may be caused, at least partially, by increased expression of long WNK1 with or without decreased expression of KS-WNK1. There are four mammalian WNK family members (1). WNK1, the first member identified, is Ͼ2,100 amino acids long (2). It contains an Ϸ270-aa kinase domain located near the amino terminus (e.g., amino acids 218-491 of the rat WNK1). WNK2, 3, and 4 are products of different genes and Ϸ1,200 to 1,600 amino acids in length (1, 2). The kinase domain of the four WNKs that share 85-90% sequence identity are unique in having the catalytic lysine located in the subdomain I instead of the conserved subdomain II of most protein kinases (1-3). Other conserved domains of WNK kinases include an autoinhibitory domain, 1-2 coiled-coil domains, and multiple PXXP prolinerich motifs for potential protein-protein interaction (1-4). Beyond the aforementioned conserved domains͞motifs, sequence identity among the four WNKs is much lower and few homologous regions exist.Pseudohypoaldosteronism type II (PHA II) is an autosomaldominant disease characterized by hypertension and hyperkalemia (5). Recently, Wilson et al. (6) reported that mutations of WNK1 and WNK4 cause PHA II. Mutations in the WNK1 gene are large deletions of the first intron leading to increased expression. Mutations in the WNK4 gene are missense mutations in the coding sequence outside the protein kinase domain. Several recent studies have examined the mechanisms for hypertension and hyperkalemia in PHA II patients. WNK4 inhibits the activity of the sodium chloride cotransporter. WNK4 mutants that cause disease fail to inhibit the sodium chloride cotransporter, suggesting that an increase in sodium chloride cotransporter activity in the distal convoluted tubule is a cause of hypertens...

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mentioning

confidence: 99%

Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms

Lazrak

Liu

Huang³

2006

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

161

207

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“…Molecular biology and patch-clamp experiments have identified several types of K channels in the apical membrane such as the Ca 2ϩ -dependent maxi-K channel (9), voltage-gated K channel (38), and ROMK (Kir1.1) (12). Although they all could be involved in K secretion (19,37,38), it is generally accepted that ROMK is mainly responsible for K secretion under normal physiological conditions (11). Furthermore, studies performed in ROMKnull mice have firmly established that ROMK channels are the key component of the SK channels in the native CCD because no SK channel activity was observed in the CCD from ROMKnull mice (20,21).…”

mentioning

confidence: 99%

“…Factors such as dietary K intake play a key role in regulating channel activity in the CCD (11,32): high K intake increases, whereas low K intake decreases, SK channel activity in the CCD. We have previously demonstrated that low K intake stimulates the expression of Src family protein tyrosine kinase (PTK) and that inhibition of PTK increases SK channel activity (33,34).…”

mentioning

confidence: 99%

Inhibition of phosphatidylinositol 3-kinase stimulates activity of the small-conductance K channel in the CCD

Li¹,

Wei²,

Babilonia³

et al. 2006

American Journal of Physiology-Renal Physiology

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We used Western blotting to examine the expression of phosphatidylinositol 3-kinase (PI3K) in the renal cortex and outer medulla and employed the patch-clamp technique to study the effect of PI3K on the ROMK-like small-conductance K (SK) channels in the cortical collecting duct (CCD). Low K intake increased the expression of the 110-kDa ␣-subunit (p110␣) of PI3K compared with rats on a normal-K diet. Because low K intake increases superoxide levels (2), the possibility that increases in superoxide anions may be responsible for the effect of low K intake on the expression of PI3K is supported by finding that addition of H 2O2 stimulates the expression of p110␣ in M1 cells. Inhibition of PI3K with either wortmannin or LY-294002 significantly increased channel activity in the CCD from rats on a K-deficient (KD) diet or on a normal-K diet. The stimulatory effect of wortmannin on ROMK channel activity cannot be mimicked by inhibition of phospholipase C with U-73122. This suggests that the effect of inhibiting PI3K was not the result of increasing the phosphatidylinositol 4,5-bisphosphate level. Moreover, application of the exogenous phosphatidylinositol 3,4,5-trisphosphate analog had no effect on channel activity in excised patches. Because low K intake has been shown to increase the activity of protein tyrosine kinase (PTK), we explored the role of the interaction between PTK and PI3K in the regulation of the SK channel activity. Inhibition of PTK increased SK channel activity in the CCD from rats on a KD diet. However, addition of wortmannin did not further increase ROMK channel activity. Also, the effect of wortmannin was abolished by treatment of CCD with phalloidin. We conclude that PI3K is involved in mediating the effect of low K intake on ROMK channel activity in the CCD and that the effect of PI3K on SK channels requires the involvement of PTK and the cytoskeleton.

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“…Several K + -selective channels have been identifi ed and/or described, but there is no consensus on which, if any, is the dominant form ( Hebert et al, 2005 ). This may refl ect the diversity of K + channels in any one epithelium or differences among tissues.…”

Section: Basolateral K + Permeabilitymentioning

confidence: 99%