Cell Surface Expression of the ROMK (Kir 1.1) Channel Is Regulated by the Aldosterone-induced Kinase, SGK-1, and Protein Kinase A

Yoo, Dana; Kim, Bo Young; Campo, Christine K.; Nance, Latreece; King, Amanda; Maouyo, Djikolngar; Welling, Paul A.

doi:10.1074/jbc.m212301200

Cited by 159 publications

(158 citation statements)

References 54 publications

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“…In the CCD (27) and the CNT (28), ROMK is up-regulated in the apical membrane by a high K diet. Aldosterone increases ROMK in the apical membrane of the rat CCD (29). Consistent with the present results, a high K diet induced charybdotoxin-sensitive K secretion in the late distal tubule of the mouse as assessed by micropuncture (30).…”

Section: Discussionsupporting

confidence: 78%

Hypertension of Kcnmb1 ^−/− is linked to deficient K secretion and aldosteronism

Grimm

Irsik

Settles

et al. 2009

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

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Mice lacking the ␤1-subunit (gene, Kcnmb1; protein, BK-␤1) of the large Ca-activated K channel (BK) are hypertensive. This phenotype is thought to result from diminished BK currents in vascular smooth muscle where BK-␤1 is an ancillary subunit. However, the ␤1-subunit is also expressed in the renal connecting tubule (CNT), a segment of the aldosterone-sensitive distal nephron, where it associates with BK and facilitates K secretion. Because of the correlation between certain forms of hypertension and renal defects, particularly in the distal nephron, it was determined whether the hypertension of Kcnmb1 ؊/؊ has a renal origin. We found that Kcnmb1 ؊/؊ are hypertensive, volume expanded, and have reduced urinary K and Na clearances. These conditions are exacerbated when the animals are fed a high K diet (5% K; HK). Supplementing HK-fed Kcnmb1 ؊/؊ with eplerenone (mineralocorticoid receptor antagonist) corrected the fluid imbalance and more than 70% of the hypertension. Finally, plasma [aldo] was elevated in Kcnmb1 ؊/؊ under basal conditions (control diet, 0.6% K) and increased significantly more than wild type when fed the HK diet. We conclude that the majority of the hypertension of Kcnmb1 ؊/؊ is due to aldosteronism, resulting from renal potassium retention and hyperkalemia.adrenal medulla ͉ BK ͉ eplerenone ͉ mineralcorticoid ͉ volume expansion

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Section: Discussionsupporting

confidence: 78%

Hypertension of Kcnmb1 ^−/− is linked to deficient K secretion and aldosteronism

Grimm

Irsik

Settles

et al. 2009

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

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“…We and others have observed that only a small fraction of ROMK1 is actually expressed in the plasma membrane of COS7 cells transfected with ROMK1 (23,24). Fig.…”

Section: Inhibition Of Ubiquitination Increases the Surface Expressiomentioning

confidence: 99%

ROMK1 channel activity is regulated by monoubiquitination

Lin

Sterling

Wang

et al. 2005

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

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The ubiquitination of proteins can signal their degradation, modify their activity or target them to specific membranes or cellular organelles. Here, we show that monoubiquitination regulates the plasma membrane abundance and function of the potassium channel, ROMK. Immunoprecipitation of proteins obtained from renal cortex and outer medulla with ROMK antibody revealed that this channel was monoubiquitinated. To determine the ubiquitin binding site on ROMK1, all intracellular lysine (Lys) residues of ROMK1 were individually mutated to arginine (Arg), and a twoelectrode voltage clamp was used to measure the ROMK1 channel activity in Xenopus oocytes. ROMK1 channel activity increased from 8.1 to 27.2 A only when Lys-22 was mutated to Arg. Furthermore, Western blotting failed to detect the ubiquitinated ROMK1 in oocytes injected with R1K22R. Patch-clamp experiments showed that biophysical properties of R1K22R were identical to those of wild-type ROMK1. Although total protein expression levels of GFP-ROMK1 and GFP-R1K22R in oocytes were similar, confocal microscopy showed that the surface fluorescence intensity in oocytes injected with GFP-R1K22R was higher than that of GFP-ROMK1. In addition, biotin labeling of ROMK1 and R1K22R proteins expressed in HEK293 cells showed increased surface expression of the Lys-22 mutant channel. Finally, expression of R1K22R in COS7 cells significantly stimulated the surface expression of ROMK1. We conclude that ROMK1 can be monoubiquitinated and that Lys-22 is an ubiquitin-binding site. Thus, monoubiquitination of ROMK1 regulates channel activity by reducing the surface expression of channel protein. This finding implicates the linking of a single ubiquitin molecule to channels as an important posttranslational regulatory signal.ubiquitination ͉ inwardly rectifying K channel (Kir.11) ͉ K recycling ͉ collecting duct ͉ thick ascending limb R OMK (KCNJ1) channel is an inwardly rectifying K channel located in the apical membrane of the thick ascending limb (TAL) and of the cortical collecting duct (CCD) (1). ROMK channels in the TAL are responsible for K recycling across the apical membrane and K recycling is essential for maintaining normal function of Na͞Cl͞K cotransporter (2). The importance of ROMK in K recycling in the TAL has been best demonstrated by the finding that loss-function mutations in ROMK cause salt wasting and metabolic alkalosis (Barter's syndrome) (3). ROMK is also responsible for K secretion in the CCD. Although the Ca 2ϩ -dependent maxi K channel has been shown to be involved in K secretion when urinary flow rate in the CCD is high (4, 5), ROMK channels play a principal role in K secretion under normal tubule flow (1, 2, 6).ROMK channel activity is regulated by hormones and dietary K intake by modulating the number of channels in the apical membrane (1,7,8). We and others have demonstrated that stimulation of V2 receptor with vasopressin or an increase in dietary K content increases the apical ROMK channel number in the CCD (9, 10). In contrast, low K intake decreas...

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“…34 It has also been suggested that sgk1 may regulate ENaC subunit gene expression. 35 Sgk1 has also been reported to phosphorylate the Kir1.1 (ROMK) subtype of inward rectifier K ϩ channel, thereby increasing channel density; 36 such an effect may contribute to the kaliuretic action of aldosterone. The mild aldosterone-resistant phenotype of the sgk1 null mice is in contrast to that of MR or ENaC-subunit null mice; 29,37 this may indicate that sgk1 is not the exclusive effector of aldosterone action or that other isoforms of sgk, sgk2, and sgk3, although not normally regulated by corticosteroids, may be able to compensate in this model.…”

Section: Epithelial Aldosterone-induced Proteinsmentioning

confidence: 99%

Mechanisms of Mineralocorticoid Action

Fuller¹,

Young²

2005

Hypertension

277

169

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Abstract-Sodium transport in epithelial tissues is regulated by the physiological mineralocorticoid aldosterone. The response to aldosterone is mediated by the mineralocorticoid receptor (MR), for which the crystal structure of the ligand-binding domain has recently been established. The classical mode of action for this receptor involves the regulation of gene transcription. Several genes have now been shown to be regulated by aldosterone in epithelial tissues. Of these, the best characterized is serum-and glucocorticoid-regulated kinase, which increases sodium influx through the epithelial sodium channel. Turnover of these channels in the cell membrane is mediated by Nedd4 -2, a ubiquitin protein ligase; serum-and glucocorticoid-regulated kinase interacts with and phosphorylates Nedd4 -2, thereby rendering it unable to bind the sodium channels. Key Words: aldosterone Ⅲ sodium channels Ⅲ fibrosis T he isolation of aldosterone just over 50 years ago established it as the primary physiological mineralocorticoid. 1 Sodium transport, and hence salt balance, is regulated by a number of mechanisms; however, aldosterone has a critical role. Aldosterone exerts its effects on the distal nephron (and colon) as the last point of sodium reabsorption; it is thus the final arbiter. 2,3 The importance of aldosterone in the maintenance of sodium homeostasis is seen in a series of monogenetic causes of hypertension, 2 in Conn's syndrome, and in disorders in which mineralocorticoid action is compromised with consequent, life-threatening salt losses. 3 Although other pathophysiological consequences of aldosterone excess were identified by Selye 4 over 60 years ago, their significance has only recently been appreciated. Evidence from the Randomized ALdactone Evaluation Study (RALES) and EPlerenone neuroHormonal Efficacy and SUrvival Study (EPHESUS) trials of beneficial effects of mineralocorticoid antagonist therapy on morbidity and mortality in cardiac failure has focused attention beyond the kidney to effects of mineralocorticoids more broadly in the cardiovascular system. 5 Although an understanding of the molecular basis of aldosterone action has tended to lag behind advances in the biology of other steroid hormones, the last decade has seen significant advances toward an understanding of the mechanisms of mineralocorticoid action. The primary mediator of the response to aldosterone is the mineralocorticoid receptor (MR), the ligand-binding domain (LBD) of which has been recently crystallized. 6 -8 Although the MR primarily acts as a transcription factor, recent evidence suggests that it may also mediate nongenomic (or nonnuclear) activation of second messenger pathways. In addition, there is a growing body of evidence that some actions of aldosterone may involve a receptor other than the MR. The cellular and molecular mediators, including proteins induced by aldosterone, have been characterized in sodium transporting epithelia; however, the critical molecular events in the vasculature remain to be determined. In this brief r...

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Cell Surface Expression of the ROMK (Kir 1.1) Channel Is Regulated by the Aldosterone-induced Kinase, SGK-1, and Protein Kinase A

Cited by 159 publications

References 54 publications

Hypertension of Kcnmb1 ^−/− is linked to deficient K secretion and aldosteronism

Hypertension of Kcnmb1 ^−/− is linked to deficient K secretion and aldosteronism

ROMK1 channel activity is regulated by monoubiquitination

Mechanisms of Mineralocorticoid Action

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Cell Surface Expression of the ROMK (Kir 1.1) Channel Is Regulated by the Aldosterone-induced Kinase, SGK-1, and Protein Kinase A

Cited by 159 publications

References 54 publications

Hypertension of Kcnmb1 −/− is linked to deficient K secretion and aldosteronism

Hypertension of Kcnmb1 −/− is linked to deficient K secretion and aldosteronism

ROMK1 channel activity is regulated by monoubiquitination

Mechanisms of Mineralocorticoid Action

Contact Info

Product

Resources

About

Hypertension of Kcnmb1 ^−/− is linked to deficient K secretion and aldosteronism

Hypertension of Kcnmb1 ^−/− is linked to deficient K secretion and aldosteronism