Hyperaldosteronism, a common cause of hypertension, is strongly connected to Na+, K+, and Mg2+ dysregulation. Owing to its steroidal structure, aldosterone is an active transcriptional modifier when bound to the mineralocorticoid receptor (MR) in cells expressing the enzyme 11β-hydroxysteroid dehydrogenase 2, such as those comprising the aldosterone-sensitive distal nephron (ASDN). One such up-regulated protein, the ubiquitous serum and glucocorticoid regulated kinase 1 (SGK1), has the capacity to modulate the surface expression and function of many classes of renal ion channels, including those that transport Na+ (ENaC), K+ (ROMK/BK), Ca2+ (TRPV4/5/6), Mg2+ (TRPM7/6), and Cl (ClC-K, CFTR). Here, we discuss the mechanisms by which ASDN expressed channels are up-regulated by SGK1, while highlighting newly discovered pathways connecting aldosterone to nonselective cation channels that are permeable to Mg2+ (TRPM7) or Ca2+ (TRPV4).

Introduction

In 2017, hypertensive blood pressure thresholds were lowered such that stage 1 hypertension commences at 130 mmHg (systolic) and/or 80 mmHg (diastolic) [1]; down from 140 mmHg/90 mmHg [2]. Prior to these changes, global data showed hypertensive rates of 22–30% in the total population [26], however with the more stringent definitions, these rates will no doubt climb. Moreover, the prevalence of hypertension is expected to further increase over time due to increasing rates of obesity and a progressively aging demographic [3].

Clinically, hyperaldosteronism is often observed in resistant hypertension [4] and is a common cause of secondary hypertension [58]. This is of major significance because hyperaldosteronism is associated with a plethora of cardiovascular comorbidities and is hallmarked by electrolyte dysregulation [9]. Moreover, drugs that target aldosterone and its mineralocorticoid receptor, such as spironolactone and eplerenone, are increasingly being used in the management of various pathologies, including hypertension, heart failure, arrhythmias and renal disease [10,11]. Therefore, it is critically important that the ion regulatory pathways of aldosterone are fully understood to understand the unintended consequences of aldosterone-related treatments.

Ion transport abnormalities in hyperaldosteronism are to be expected, as the earliest research into aldosterone showed that the steroid hormone decreases the excretion of Na+ [12] and increases the excretion of K+ and H+ [13]. Mechanistically, most effects of aldosterone are exerted through the mineralocorticoid receptor (MR), to which aldosterone binds [14]. However, the MR has equal affinity for aldosterone and glucocorticoids [15], a surprising observation since glucocorticoid plasma concentrations are 100–1000 times higher than aldosterone concentrations [16]. To maintain aldosterone sensitivity, aldosterone-sensitive cells express 11β-hydroxysteroid dehydrogenase 2 [17], which converts cortisol to cortisone [18], preventing cortisol from interacting with the MR [17]. Within the kidney, immunohistochemical and immunocytochemical experiments have shown that 11β-hydroxysteroid dehydrogenase localizes to three consecutive segments: the distal convoluted tubule (DCT), connecting tubule (CNT), and cortical collecting duct (CCD) [19,20]. In some species, where the DCT has been subdivided into the DCT1 and DCT2 based on protein expression [21,22], the aldosterone-sensitive distal nephron (ASDN) would commence in DCT2 [19].

Aldosterone and genomic signaling

The discovery of the high affinity aldosterone receptor, the MR [14], and 11β-hydroxysteroid dehydrogenase in renal (distal tubular) cells [17,19,20,23] opened the possibility that aldosterone-MR signaling may affect ion transporters, of which Na+ transporters were the first to be studied. In the kidney, aldosterone increases the transcription of the basolateral Na+/K+-ATPase [24] and the apical epithelial Na+ channel (ENaC) [25]. Synthesis of channels and pumps were classified as late effects since they were only detected after 20 h of 1 μM aldosterone exposure [26,27]. Short-term mechanisms have also been identified, as increases in Na+ transport were observed as early as 2.5 h after aldosterone application in cell-based studies. For apical ENaC, 1.5 μM aldosterone increased channel open time, subsequently increasing Na+ transport in A6 (amphibian) kidney cells [28]. For the basolateral Na+/K+-ATPase, 1 μM aldosterone increased the activity of the Na+/K+-ATPase at physiological [Na+]i [26]. Surprisingly, this response was dependent on protein synthesis since cycloheximide, an inhibitor of protein translation [29], blocked the effect [26]. It was speculated that the MR may transcriptionally up-regulate activators and repressors capable of short-term effects on aldosterone targets.

A83, the A6 (amphibian renal cell) equivalent of serum and glucocorticoid regulated kinase 1 (SGK1), was discovered as an aldosterone responsive protein, since 100 nM aldosterone increased A83 mRNA and protein expression. In addition, SGK1 mRNA significantly increased in the distal cortical nephron of aldosterone treated rats (50 μg/100 g), implicating its role in mammalian function. Furthermore, when SGK1 was coexpressed with ENaC in Xenopus oocytes, macroscopic current increased 7-fold [30]. Since this pioneering study, researchers have connected aldosterone-stimulated SGK1 to many ion channels, including those expressed in the ASDN. Therefore, the purpose of this review is to provide a comprehensive overview of the mechanisms by which aldosterone-MR-SGK1 affect ion channel abundance and/or function, while discussing the present limitations of the literature.

Na+ channels

There are many regulatory mechanisms whereby SGK1 increases the function of ENaC (Figure 1). First, SGK1 phosphorylates Ser444 and Ser338 of the E3 ubiquitin ligase ‘Neural precursor cell-expressed developmentally down-regulated protein’ (Nedd) 4-2, which reduces the affinity of Nedd4-2 for ENaC [31,32], and increases the affinity of Nedd4-2 for 14-3-3 [33]. When not phosphorylated, Nedd4-2 interacts with the proline-rich segments of ENaC, causing channel ubiquitination and subsequent internalization from the plasma membrane [34]. By diminishing the Nedd4-2/ENaC interaction and promoting the Nedd4-2/14-3-3 interaction, SGK1 indirectly decreases ENaC internalization, and thus increases ENaC expression at the plasma membrane (Figure 1; pathway 3).

Schematic of aldosterone, SGK1, and ENaC interactions

Figure 1
Schematic of aldosterone, SGK1, and ENaC interactions

Aldosterone freely crosses phospholipid membranes and binds to the cytosolic mineralocorticoid receptor (MR) (1). The aldo/MR complex translocates to the nucleus, binds to specialized hormone response elements (HREs), and promotes the transcription of aldosterone-regulated genes, including SGK1, which is translated into protein (2). Newly synthesized SGK1 up-regulates ENaC activity through several distinct pathways that reduce ENaC ubiquitination through bi-phosphorylation of Nedd4-2 (3), prevent ENaC endocytosis by phosphorylation of WNK4 (4), recruit silent ENaC channels to active ones by direct phosphorylation (5), and inhibit the transcriptional repressor complex Dot1a–AF9 via phosphorylation of AF9 (6).

Figure 1
Schematic of aldosterone, SGK1, and ENaC interactions

Aldosterone freely crosses phospholipid membranes and binds to the cytosolic mineralocorticoid receptor (MR) (1). The aldo/MR complex translocates to the nucleus, binds to specialized hormone response elements (HREs), and promotes the transcription of aldosterone-regulated genes, including SGK1, which is translated into protein (2). Newly synthesized SGK1 up-regulates ENaC activity through several distinct pathways that reduce ENaC ubiquitination through bi-phosphorylation of Nedd4-2 (3), prevent ENaC endocytosis by phosphorylation of WNK4 (4), recruit silent ENaC channels to active ones by direct phosphorylation (5), and inhibit the transcriptional repressor complex Dot1a–AF9 via phosphorylation of AF9 (6).

Second, SGK1 phosphorylates ‘kinase with no lysine’ (WNK)4 at Ser1169, removing the inhibitory action of WNK4 on ENaC (Figure 1; pathway 4) [35]. Patch clamp studies of the WNK4/ENaC mechanism further showed that WNK4 reduces ENaC current by 50% [36]. Surprisingly, it was observed that the C-terminus of ENaC must be present for the modulation to occur, leading to speculation that Nedd4-2 is involved in the cascade. However, more recent research has indicated that WNK4 decreases the surface expression of ENaC in a Nedd4-2 independent manner, as the C-terminal proline rich motifs of ENaC are not required for WNK4 inhibition [37].

Third, SGK1 is suggested to directly phosphorylate α-ENaC, increasing ENaC electrophysiological function by 2- to 3-fold (Figure 1; pathway 5). However, this response did not affect open channel probability, and since experiments were performed in outside-out macropatches, the authors hypothesized it was due to the conversion of silent channels into active channels. In addition, mutation of Ser621 at the C-terminus of α-ENaC abolished the SGK1 effect [38], which is further interesting because Ser621 represents the terminal amino acid of the SGK consensus sequence [38,39]. Thus, SGK1 may have a direct regulatory site on α-ENaC.

Fourth, SGK1 may directly increase the transcription of αENaC by disrupting the transcriptional repressor protein complex histone H3 Lys70 methyltransferase ‘disruptor of telomeric silencing alternative splice variant a’ (Dot1a)–‘ALL1-fused gene from chromosome 9’ (AF9), via phosphorylation of Ser435 on AF9 (Figure 1; pathway 6) [40]. However, the authors noted that the Dot1a–AF9 interaction was only impaired, not prevented, by SGK1 phosphorylation and that AF9 still bound to the αENaC promoter. Thus, it was concluded that SGK1 may only be a partial component of the mechanism responsible for the inhibition of the Dot1a–AF9 complex.

K+ channels

SGK1 also interacts with the renal outer medullary K+ channel (ROMK); an apically located [41,42] K+ secretory channel [43] of the distal nephron [44]. Prior to discussing this interaction, it is important to review the nomenclature of the ROMK proteins. ROMK is a three-member splice variant family, where differences between splice variants occur at the mRNA 5′-coding and 3′-noncoding regions [44]. With regard to the 5′-coding region (the N-terminus), ROMK1 contains two predicted targets of PKC phosphorylation (Ser4 and Thr17), ROMK2 is a truncated protein that lacks both of these sites, and ROMK3 has an extended N-terminus with a PKC-targeting threonine residue, but no equivalent serine residue [44]. These structural differences alter ROMK regulation, as ROMK1 current was inhibited by PKC through phosphorylation of Ser4, whereas the activities of ROMK2 and ROMK3 were unaffected [45]. There are also differences in the expression of each splice variant, however all three are expressed in the rat ASDN. Specifically, the DCT expresses ROMK2/3, the CNT expresses ROMK2, and the CCD expresses ROMK1/2 [44].

In cell-based experiments using exogenous ROMK1 or ROMK2, SGK1 altered ROMK function/expression through three distinct mechanisms (Figure 2). First, SGK1 phosphorylated ROMK1 at Ser44, and this was correlated with increased plasma membrane abundance of ROMK1 [46], an effect further dependent on the trafficking/transport protein Na+/H+ exchange regulatory factor 2 (NHERF2) [47]. These findings indicate that SGK1 increases ROMK1 trafficking, resulting in increased plasma membrane expression (Figure 2; pathway 1). Second, Ser44 phosphorylation shifts the pH sensitivity/activation of ROMK1 to more acidic values, increasing electrophysiological function at cytosolic pH 6.6–7.3 (Figure 2; pathway 2) [48]. Third, phosphorylation of Ser1169 [35] and Ser1196 [49] on WNK4 by SGK1 prevents clathrin-dependent endocytosis of ROMK2 (via the C-terminal NPXY-like motif), increasing the plasma membrane expression of ROMK2 (Figure 2; pathway 3) [50]. Importantly, as Ser44 and the C-terminus of ROMK are downstream to the reported N-terminal differences between ROMK1-3 [44], these conclusions may apply to all ROMK splice variants, however this awaits confirmation.

Schematic of aldosterone, SGK1, and ROMK interactions

Figure 2
Schematic of aldosterone, SGK1, and ROMK interactions

Following an identical cellular entry and SGK1 synthetic pathway discussed for ENaC (Figure 1), aldosterone (through SGK1) up-regulates ROMK activity through three distinct pathways: increased NHERF2-dependent ROMK trafficking via direct phosphorylation of ROMK (1), increased channel function by direct phosphorylation of the same ROMK site (2), and decreased ROMK endocytosis via bi-phosphorylation of WNK4 (3).

Figure 2
Schematic of aldosterone, SGK1, and ROMK interactions

Following an identical cellular entry and SGK1 synthetic pathway discussed for ENaC (Figure 1), aldosterone (through SGK1) up-regulates ROMK activity through three distinct pathways: increased NHERF2-dependent ROMK trafficking via direct phosphorylation of ROMK (1), increased channel function by direct phosphorylation of the same ROMK site (2), and decreased ROMK endocytosis via bi-phosphorylation of WNK4 (3).

The large conductance Ca2+-activated K+ channel (BK), also termed Maxi-K+, is a K+ secretory channel expressed throughout the ASDN [5156]. BK is primarily stimulated by flow [57] and high K+ diets [5860], although stimulation of BK by membrane stretch has also been reported [61]. An initial study by Estilo et al. [60] suggested aldosterone did not regulate BK in the rabbit CCD. However, it was concurrently reported that aldosterone increased BK mRNA, luminal expression, and K+ secretion in the mouse colon [62]. An important difference between these studies was their method of aldosterone stimulation. The CCD study used low Na+ diets, whereas the colonic study used high K+ diets. Subsequently, in a mouse study where aldosterone was stimulated by high K+ diets, it was determined that MR blockade could severely blunt BK expression [63]. A follow-up study by this same group revealed that even with a low Na+ and high K+ diet, adrenalectamized mice with low aldosterone supplementation had lower apical and total BK expression than control, confirming the necessity of aldosterone for BK up-regulation [64].

The effects of SGK1 on BK function are only beginning to be examined. In a 2017 study comparing control and SGK1 knockout mice, BK whole-cell currents were unaffected, even when animals were fed high K+ diets [65]. In addition, ROMK whole-cell currents, amiloride-sensitive whole-cell currents, and amiloride-sensitive Na+ excretion were also unaffected in SGK1 knockout mice fed with high K+ diets. The latter two results were surprising, as ENaC surface expression was decreased when animals were subjected to similar treatments [65]. To date, there have yet to be any studies that have examined the direct effect of SGK1 on BK plasma membrane expression.

Ca2+ channels

Ca2+ reabsorption in the ASDN occurs in part via the epithelial Ca2+ channel transient receptor potential vanilloid (TRPV)5 [6668] and its homolog TRPV6 [68,69]. TRPV5, the first to be studied, was discovered as an apical channel located in the rabbit DCT, CNT, and CCD [66]. For species which subdivide the DCT into DCT1 and DCT2, TRPV5 expression commences in DCT2 [69]. Pertaining to SGK1, coexpression of SGK1, NHERF2, and TRPV5 dramatically increased current in Xenopus oocytes. This change was accompanied by an increase in the TRPV5 surface chemiluminescence, suggesting that SGK1, along with NHERF2, increases the surface expression of TRPV5 [70,71]. The surface expression and function of TRPV6 was also increased when TRPV6 and SGK1 were coexpressed in Xenopus oocytes. This effect did not require NHERF2 [72], differentiating the response from SGK1/TRPV5 [70,71].

TRPV4 is a nonselective cation channel [73,74] expressed on apical membranes of the CNT and CCD [75]. Of relevance to the tubule, TRPV4 is activated by changes in osmolarity [7678], sheer stress [7881], and pressure [82]. Indeed, high flow rates over the mouse luminal collecting duct increased [Ca2+]i, which was abolished in TRPV4 knockout animals [75]. This capacity to increase [Ca2+]i has connected TRPV4 to the Ca2+-activated BK channel, as TRPV4 potentiators increased flow-dependent K+ secretion in wildtype animals whereas urinary K+ excretion was significantly decreased in TRPV4 knockout animals [83].

Recently, it has been demonstrated that both aldosterone and high K+ diets increase the total expression of TRPV4 in primary and immortalized mouse CCD cells [84]. It was notable that TRPV4 expression in mice treated with MR antagonists was below control, implying that aldosterone constitutively regulates TRPV4 [84]. This study further demonstrated that high K+ diets, which should induce aldosterone release [85], increased TRPV4 apical membrane expression and increased flow-mediated [Ca2+]i [84]. While SGK1-mediated effects were not explored, the authors noted that prior findings of TRPV4 phosphorylation (at Ser824) by SGK1, which increased channel activity, Ca2+ influx, and protein stability [86], would explain their aldosterone-mediated effects 84]. Thus, it is possible that aldosterone, through SGK1, increases the expression/function of TRPV4, which increases [Ca2+]i in response to sheer stress, and provides the necessary intracellular Ca2+ for BK-dependent K+ secretion.

Mg2+ channels

The relationship between aldosterone, SGK1, and Mg2+ permeable channels represents a largely unexplored field of renal electrolyte regulation. While many Mg2+ permeable channels have been identified in DCT primary cells and cell lines, such as transient receptor potential melastatin (TRPM)6 [8789], TRPM7 [8991], MagT1 [92,93], and ACDP2/CNNM2 [94], few have been studied with aldosterone. TRPM6 [87,95] and TRPM7 [91,9698] are further complex, as they comprise Mg2+ permeable, nonselective cation channels fused to a C-terminal α-kinase domain. Moreover, the α-kinase domain can be cleaved from both channels and act as a nuclear histone modifier, regulating the expression of thousands of genes [99,100]. Thus, studies examining TRPM6 or TRPM7 must account for the broad-spectrum regulatory capacity of the α-kinase domain.

Pertaining to aldosterone, we demonstrated that mice injected with aldosterone have a lower membrane to cytosol fraction of renal TRPM6 compared with control animals, an effect that was rescued when mice were fed high Mg2+ diets [101]. We have also studied TRPM7 and aldosterone, including pathways that involve SGK1. In cell-based studies using TRPM7-expressing HEK293 cells, aldosterone increased [Mg2+]i, ROS, pro-inflammatory mediator expression. Pro-inflammatory mediator expression was only observed in kinase-defective mutants, not wildtype cells [102]. Furthermore, in those same cells, aldosterone increased TRPM7 plasma membrane expression and whole-cell current in an MR and SGK1-dependent mechanism (Figure 3). This effect was abolished in the phosphotransferase inactive K1648R mutant, implying that SGK1 evokes its effects through the α-kinase domain [103].

Potential physiological consequences of aldosterone, SGK1, and TRPM7

Figure 3
Potential physiological consequences of aldosterone, SGK1, and TRPM7

Aldosterone, through induction of SGK1, increases TRPM7 plasma membrane expression and electrophysiological function via an α-kinase-dependent pathway in expression systems. In the ASDN, where tubular proton concentration is elevated and divalent cation concentrations are low, TRPM7 is likely to function as a Na+ channel (1). In tissues where aldosterone is active, extracellular cations are serum-like, and extracellular pH is near 7.4, TRPM7 is likely to function as a Zn2+, Mg2+, and Ca2+ channel (2).

Figure 3
Potential physiological consequences of aldosterone, SGK1, and TRPM7

Aldosterone, through induction of SGK1, increases TRPM7 plasma membrane expression and electrophysiological function via an α-kinase-dependent pathway in expression systems. In the ASDN, where tubular proton concentration is elevated and divalent cation concentrations are low, TRPM7 is likely to function as a Na+ channel (1). In tissues where aldosterone is active, extracellular cations are serum-like, and extracellular pH is near 7.4, TRPM7 is likely to function as a Zn2+, Mg2+, and Ca2+ channel (2).

The consequences of these mechanisms are vast given that TRPM7/6 permeability is governed by electrolytes. In circumstances where extracellular divalent cation concentrations are low and extracellular pH is acidic, such as the distal tubule, TRPM7 and TRPM6 are likely to conduct Na+ (Figure 3; pathway 1) [104,105]. However, in extracellular conditions where divalent cation concentrations and pH are serum-like, TRPM7 and TRPM6 are likely to function as nonselective cation channels with Mg2+ permeability (Figure 3; pathway 2) [88,106,107]. Further supportive of this rationale, knockout studies targeting TRPM7 or TRPM6 showed that these animals exhibited decreased renal Mg2+ excretion and increased fecal Mg2+ excretion compared with control [108,109]. While it is tempting to conclude that TRPM7 and TRPM6 function as Na+ channels in the ASDN whereas TRPM7 and TRPM6 function as divalent cation (Mg2+) channels in the intestine of the KO mice, the loss or reduction of a transcriptionally active α-kinase should severely impact cellular homeostasis. Nonetheless, the dynamic permeability properties of TRPM7 and TRPM6 must be factored into conclusions surrounding their function in aldosterone-sensitive regions.

Cl channels

The presence of pathways connecting SGK1 to Cl transport in the ASDN are less conclusive, however it is highly plausible that aldosterone, through SGK1, is capable of influencing Cl transport. By a mechanism similar to that described above for ENaC, SGK1 was shown to increase the plasma membrane expression of Cl permeable ClC-Ka/barttin [110,111] by decreasing the Nedd4-2 interaction with the PY motif of barttin in exogenously expressing Xenopus oocytes [112]. However, in the ASDN, human ClC-Kb/barttin is expressed [113], not ClC-Ka/barttin [114]. Importantly, Nedd4-2 interacts with the barttin subunit [112], and therefore it is possible that SGK1 increases the plasma membrane expression of ClC-Kb/barttin. This hypothesis is further supported by the similarity between ClC-Ka and ClC-Kb (94% sequence homology [115]), although this has yet to be demonstrated.

The mRNA of cystic fibrosis transmembrane conductance regulator (CFTR) has been identified in rabbit DCT [116], and CFTR-like currents have been electrophysiologically recorded in rabbit DCT cells [116,117]. When studied in pancreatic duct adenocarcinoma cells, wildtype CFTR and Nedd4-2 co-immunoprecipitated, implying a physical connection between the two proteins [118]. This interaction was also observed for Nedd4-2 and ΔF508-CFTR, and siRNA knockdown of Nedd4-2 acted as a rescue for ΔF508-CFTR plasma membrane expression. Furthermore, siRNA knockdown of endogenous SGK1 abolished a previously characterized pharmacological rescue of plasma membrane bound ΔF508-CFTR, indicating that SGK1/Nedd4-2 internalization mechanisms mediated the plasma membrane expression of ΔF508-CFTR. Since CFTR is expressed in the aldosterone-sensitive distal nephron, it is also possible that SGK1 modulates CFTR through Nedd4-2 ubiquitination, however this has yet to be determined.

Conclusions

Aldosterone has long been connected with ion transport and ion channel function. Historically this has emphasized ENaC and ROMK, as Na+ and K+ dyshomeostasis were some of the first symptoms associated with hyperaldosteronism. Aldosterone signaling cascades, particularly those evoking widely expressed mediators, such as SGK1, have expanded the possible classes of ion channels affected by aldosterone. It is now accepted that aldosterone, through SGK1, has the capacity to modulate ion metabolism through several ion channels, including those that regulate Na+, K+, Ca2+, Mg2+, and Cl. Unlike Na+ and K+ channels, there is a paucity of information regarding aldosterone/SGK1 effects on renal Ca2+, Mg2+, and Cl channels. Hence, there is still much to be explored in understanding the mechanistic pathways whereby aldosterone, through its mineralocorticoid receptor and downstream target SGK1, regulate ion channels in the kidney in health and disease. Recognizing that aldosterone influences electrolyte balance beyond its effects on Na+ and K+ regulation is important because perturbations in renal handling of Mg2+, Ca2+, Cl, and H+ likely influence multiple tissue systems and would impact disease management.

Author Contribution

All the authors have contributed substantially to this work.

Funding

This work was supported by the Canadian Institute of Health Research [Grant number CIHR–MOP57786 (to A.S. and R.M.T.)]; and the Canada Research Chair/Canadian Foundation for Innovation award and British Heart Foundation Chair [Grant number CH/4/29762 (to R.M.T.)].

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • ASDN

    aldosterone-sensitive distal nephron

  •  
  • BK

    large conductance Ca2+-activated K+ channel

  •  
  • CCD

    cortical collecting duct

  •  
  • CFTR

    cystic fibrosis transmembrane conductance regulator

  •  
  • CNT

    connecting tubule

  •  
  • DCT

    distal convoluted tubule

  •  
  • Dot1a–AF9

    disruptor of telomeric silencing alternative splice variant a–ALL1-fused gene from chromosome 9

  •  
  • ENaC

    epithelial sodium channel

  •  
  • MR

    mineralocorticoid receptor

  •  
  • Nedd

    neural precursor cell-expressed developmentally down-regulated protein

  •  
  • NHERF2

    Na+/H+ exchange regulatory factor 2

  •  
  • ROMK

    renal outer medullary K+ channel

  •  
  • SGK1

    serum and glucocorticoid regulated kinase 1

  •  
  • TRPM

    transient receptor potential melastatin

  •  
  • TRPV

    transient receptor potential vanilloid

  •  
  • WNK

    kinase with no lysine

References

References
1
Whelton
P.K.
,
Carey
R.M.
,
Aronow
W.S.
,
Casey
D.E.
Jr
,
Collins
K.J.
,
Dennison Himmelfarb
C.
et al. 
(
2017
)
ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines
.
J. Am. Coll. Cardiol.
,
2
Chaturvedi
S.
(
2004
)
The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure (JNC 7): is it really practical?
Natl. Med. J. India
17
,
227
[PubMed]
3
Padwal
R.S.
,
Bienek
A.
,
McAlister
F.A.
,
Campbell
N.R.
and (
2016
)
Epidemiology of hypertension in Canada: an update
.
Can. J. Cardiol.
32
,
687
694
4
Dudenbostel
T.
and
Calhoun
D.A.
(
2017
)
Use of aldosterone antagonists for treatment of uncontrolled resistant hypertension
.
Am. J. Hypertens.
30
,
103
109
[PubMed]
5
Rossi
G.P.
,
Bernini
G.
,
Caliumi
C.
,
Desideri
G.
,
Fabris
B.
,
Ferri
C.
et al. 
(
2006
)
A prospective study of the prevalence of primary aldosteronism in 1125 hypertensive patients
.
J. Am. Coll. Cardiol.
48
,
2293
2300
[PubMed]
6
Olivieri
O.
,
Ciacciarelli
A.
,
Signorelli
D.
,
Pizzolo
F.
,
Guarini
P.
,
Pavan
C.
et al. 
(
2004
)
Aldosterone to renin ratio in a primary care setting: the Bussolengo study
.
J. Clin. Endocrinol. Metab.
89
,
4221
4226
[PubMed]
7
Douma
S.
,
Petidis
K.
,
Doumas
M.
,
Papaefthimiou
P.
,
Triantafyllou
A.
,
Kartali
N.
et al. 
(
2008
)
Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study
.
Lancet
371
,
1921
1926
[PubMed]
8
Loh
K.C.
,
Koay
E.S.
,
Khaw
M.C.
,
Emmanuel
S.C.
and
Young
W.F.
Jr
(
2000
)
Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore
.
J. Clin. Endocrinol. Metab.
85
,
2854
2859
[PubMed]
9
Born-Frontsberg
E.
,
Reincke
M.
,
Rump
L.C.
,
Hahner
S.
,
Diederich
S.
,
Lorenz
R.
et al. 
(
2009
)
Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn's Registry
.
J. Clin. Endocrinol. Metab.
94
,
1125
1130
[PubMed]
10
Funder
J.W.
(
2010
)
Aldosterone, hypertension and heart failure: insights from clinical trials
.
Hypertens. Res.
33
,
872
875
[PubMed]
11
Tam
T.S.
,
Wu
M.H.
,
Masson
S.C.
,
Tsang
M.P.
,
Stabler
S.N.
,
Kinkade
A.
et al. 
(
2017
)
Eplerenone for hypertension
.
Cochrane Database Syst. Rev.
2
,
CD008996
[PubMed]
12
Barger
A.C.
,
Berlin
R.D.
and
Tulenko
J.F.
(
1958
)
Infusion of aldosterone, 9-alpha-fluorohydrocortisone and antidiuretic hormone into the renal artery of normal and adrenalectomized, unanesthetized dogs: effect on electrolyte and water excretion
.
Endocrinology
62
,
804
815
[PubMed]
13
Bartter
F.C.
(
1956
)
The role of aldosterone in normal homeostasis and in certain disease states
.
Metabolism
5
,
369
383
[PubMed]
14
Funder
J.W.
,
Feldman
D.
and
Edelman
I.S.
(
1973
)
The roles of plasma binding and receptor specificity in the mineralocorticoid action of aldosterone
.
Endocrinology
92
,
994
1004
[PubMed]
15
Krozowski
Z.S.
and
Funder
J.W.
(
1983
)
Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity
.
Proc. Natl. Acad. Sci. USA
80
,
6056
6060
16
Funder
J.W.
,
Pearce
P.T.
,
Smith
R.
and
Smith
A.I.
(
1988
)
Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated
.
Science
242
,
583
585
[PubMed]
17
Edwards
C.R.
,
Stewart
P.M.
,
Burt
D.
,
Brett
L.
,
McIntyre
M.A.
,
Sutanto
W.S.
et al. 
(
1988
)
Localisation of 11 beta-hydroxysteroid dehydrogenase–tissue specific protector of the mineralocorticoid receptor
.
Lancet
2
,
986
989
[PubMed]
18
Lakshmi
V.
and
Monder
C.
(
1985
)
Evidence for independent 11-oxidase and 11-reductase activities of 11 beta-hydroxysteroid dehydrogenase: enzyme latency, phase transitions, and lipid requirements
.
Endocrinology
116
,
552
560
[PubMed]
19
Bostanjoglo
M.
,
Reeves
W.B.
,
Reilly
R.F.
,
Velazquez
H.
,
Robertson
N.
,
Litwack
G.
et al. 
(
1998
)
11Beta-hydroxysteroid dehydrogenase, mineralocorticoid receptor, and thiazide-sensitive Na-Cl cotransporter expression by distal tubules
.
J. Am. Soc. Nephrol.
9
,
1347
1358
[PubMed]
20
Campean
V.
,
Kricke
J.
,
Ellison
D.
,
Luft
F.C.
and
Bachmann
S.
(
2001
)
Localization of thiazide-sensitive Na(+)-Cl(−) cotransport and associated gene products in mouse DCT
.
Am. J. Physiol. Renal Physiol.
281
,
F1028
F1035
[PubMed]
21
Loffing
J.
,
Loffing-Cueni
D.
,
Valderrabano
V.
,
Klausli
L.
,
Hebert
S.C.
,
Rossier
B.C.
et al. 
(
2001
)
Distribution of transcellular calcium and sodium transport pathways along mouse distal nephron
.
Am. J. Physiol. Renal Physiol.
281
,
F1021
F107
[PubMed]
22
Schmitt
R.
,
Ellison
D.H.
,
Farman
N.
,
Rossier
B.C.
,
Reilly
R.F.
,
Reeves
W.B.
et al. 
(
1999
)
Developmental expression of sodium entry pathways in rat nephron
.
Am. J. Physiol.
276
,
F367
F381
[PubMed]
23
Farman
N.
and
Bonvalet
J.P.
(
1983
)
Aldosterone binding in isolated tubules. III. Autoradiography along the rat nephron
.
Am. J. Physiol.
245
,
F606
F614
[PubMed]
24
Verrey
F.
,
Kraehenbuhl
J.P.
and
Rossier
B.C.
(
1989
)
Aldosterone induces a rapid increase in the rate of Na,K-ATPase gene transcription in cultured kidney cells
.
Mol. Endocrinol.
3
,
1369
1376
[PubMed]
25
May
A.
,
Puoti
A.
,
Gaeggeler
H.P.
,
Horisberger
J.D.
and
Rossier
B.C.
(
1997
)
Early effect of aldosterone on the rate of synthesis of the epithelial sodium channel alpha subunit in A6 renal cells
.
J. Am. Soc. Nephrol.
8
,
1813
1822
[PubMed]
26
Beron
J.
,
Mastroberardino
L.
,
Spillmann
A.
and
Verrey
F.
(
1995
)
Aldosterone modulates sodium kinetics of Na,K-ATPase containing an alpha 1 subunit in A6 kidney cell epithelia
.
Mol. Biol. Cell
6
,
261
271
[PubMed]
27
Beron
J.
and
Verrey
F.
(
1994
)
Aldosterone induces early activation and late accumulation of Na-K-ATPase at surface of A6 cells
.
Am. J. Physiol.
266
,
C1278
C1290
[PubMed]
28
Kemendy
A.E.
,
Kleyman
T.R.
and
Eaton
D.C.
(
1992
)
Aldosterone alters the open probability of amiloride-blockable sodium channels in A6 epithelia
.
Am. J. Physiol.
263
,
C825
C837
[PubMed]
29
Siegel
M.R.
and
Sisler
H.D.
(
1963
)
Inhibition of protein synthesis in vitro by cycloheximide
.
Nature
200
,
675
676
[PubMed]
30
Chen
S.Y.
,
Bhargava
A.
,
Mastroberardino
L.
,
Meijer
O.C.
,
Wang
J.
,
Buse
P.
et al. 
(
1999
)
Epithelial sodium channel regulated by aldosterone-induced protein sgk
.
Proc. Natl. Acad. Sci. USA
96
,
2514
2519
31
Debonneville
C.
,
Flores
S.Y.
,
Kamynina
E.
,
Plant
P.J.
,
Tauxe
C.
,
Thomas
M.A.
et al. 
(
2001
)
Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression
.
EMBO J.
20
,
7052
7059
[PubMed]
32
Snyder
P.M.
,
Olson
D.R.
and
Thomas
B.C.
(
2002
)
Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel
.
J. Biol. Chem.
277
,
5
8
[PubMed]
33
Bhalla
V.
,
Daidie
D.
,
Li
H.
,
Pao
A.C.
,
LaGrange
L.P.
,
Wang
J.
et al. 
(
2005
)
Serum- and glucocorticoid-regulated kinase 1 regulates ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 by inducing interaction with 14-3-3
.
Mol. Endocrinol.
19
,
3073
3084
[PubMed]
34
Staub
O.
,
Dho
S.
,
Henry
P.
,
Correa
J.
,
Ishikawa
T.
,
McGlade
J.
et al. 
(
1996
)
WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome
.
EMBO J.
15
,
2371
2380
[PubMed]
35
Ring
A.M.
,
Leng
Q.
,
Rinehart
J.
,
Wilson
F.H.
,
Kahle
K.T.
,
Hebert
S.C.
et al. 
(
2007
)
An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis
.
Proc. Natl. Acad. Sci. USA
104
,
4025
4029
36
Ring
A.M.
,
Cheng
S.X.
,
Leng
Q.
,
Kahle
K.T.
,
Rinehart
J.
,
Lalioti
M.D.
et al. 
(
2007
)
WNK4 regulates activity of the epithelial Na+ channel in vitro and in vivo
.
Proc. Natl. Acad. Sci. USA
104
,
4020
4024
37
Yu
L.
,
Cai
H.
,
Yue
Q.
,
Alli
A.A.
,
Wang
D.
,
Al-Khalili
O.
et al. 
(
2013
)
WNK4 inhibition of ENaC is independent of Nedd4-2-mediated ENaC ubiquitination
.
Am. J. Physiol. Renal Physiol.
305
,
F31
F41
[PubMed]
38
Diakov
A.
and
Korbmacher
C.
(
2004
)
A novel pathway of epithelial sodium channel activation involves a serum- and glucocorticoid-inducible kinase consensus motif in the C terminus of the channel's alpha-subunit
.
J. Biol. Chem.
279
,
38134
38142
[PubMed]
39
Diakov
A.
,
Nesterov
V.
,
Mokrushina
M.
,
Rauh
R.
and
Korbmacher
C.
(
2010
)
Protein kinase B alpha (PKBalpha) stimulates the epithelial sodium channel (ENaC) heterologously expressed in Xenopus laevis oocytes by two distinct mechanisms
.
Cell. Physiol. Biochem.
26
,
913
924
[PubMed]
40
Zhang
W.
,
Xia
X.
,
Reisenauer
M.R.
,
Rieg
T.
,
Lang
F.
,
Kuhl
D.
et al. 
(
2007
)
Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha
.
J. Clin. Invest.
117
,
773
783
[PubMed]
41
Kohda
Y.
,
Ding
W.
,
Phan
E.
,
Housini
I.
,
Wang
J.
,
Star
R.A.
et al. 
(
1998
)
Localization of the ROMK potassium channel to the apical membrane of distal nephron in rat kidney
.
Kidney Int.
54
,
1214
1223
[PubMed]
42
Wade
J.B.
,
Fang
L.
,
Coleman
R.A.
,
Liu
J.
,
Grimm
P.R.
,
Wang
T.
et al. 
(
2011
)
Differential regulation of ROMK (Kir1.1) in distal nephron segments by dietary potassium
.
Am. J. Physiol. Renal Physiol.
300
,
F1385
F1393
[PubMed]
43
Frindt
G.
and
Palmer
L.G.
(
1989
)
Low-conductance K channels in apical membrane of rat cortical collecting tubule
.
Am. J. Physiol.
256
,
F143
F151
[PubMed]
44
Boim
M.A.
,
Ho
K.
,
Shuck
M.E.
,
Bienkowski
M.J.
,
Block
J.H.
,
Slightom
J.L.
et al. 
(
1995
)
ROMK inwardly rectifying ATP-sensitive K+ channel. II. Cloning and distribution of alternative forms
.
Am. J. Physiol.
268
,
F1132
F1140
[PubMed]
45
Macica
C.M.
,
Yang
Y.
,
Lerea
K.
,
Hebert
S.C.
and
Wang
W.
(
1998
)
Role of the NH2 terminus of the cloned renal K+ channel, ROMK1, in arachidonic acid-mediated inhibition
.
Am. J. Physiol.
274
,
F175
F181
[PubMed]
46
Yoo
D.
,
Kim
B.Y.
,
Campo
C.
,
Nance
L.
,
King
A.
,
Maouyo
D.
et al. 
(
2003
)
Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase A
.
J. Biol. Chem.
278
,
23066
23075
[PubMed]
47
Yun
C.C.
,
Palmada
M.
,
Embark
H.M.
,
Fedorenko
O.
,
Feng
Y.
,
Henke
G.
et al. 
(
2002
)
The serum and glucocorticoid-inducible kinase SGK1 and the Na+/H+ exchange regulating factor NHERF2 synergize to stimulate the renal outer medullary K+ channel ROMK1
.
J. Am. Soc. Nephrol.
13
,
2823
2830
[PubMed]
48
Palmada
M.
,
Embark
H.M.
,
Wyatt
A.W.
,
Bohmer
C.
and
Lang
F.
(
2003
)
Negative charge at the consensus sequence for the serum- and glucocorticoid-inducible kinase, SGK1, determines pH sensitivity of the renal outer medullary K+ channel, ROMK1
.
Biochem. Biophys. Res. Commun.
307
,
967
972
[PubMed]
49
Rozansky
D.J.
,
Cornwall
T.
,
Subramanya
A.R.
,
Rogers
S.
,
Yang
Y.F.
,
David
L.L.
et al. 
(
2009
)
Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway
.
J. Clin. Invest.
119
,
2601
2612
[PubMed]
50
Kahle
K.T.
,
Wilson
F.H.
,
Leng
Q.
,
Lalioti
M.D.
,
O'Connell
A.D.
,
Dong
K.
et al. 
(
2003
)
WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion
.
Nat. Genet.
35
,
372
376
[PubMed]
51
Belfodil
R.
,
Barriere
H.
,
Rubera
I.
,
Tauc
M.
,
Poujeol
C.
,
Bidet
M.
et al. 
(
2003
)
CFTR-dependent and -independent swelling-activated K+ currents in primary cultures of mouse nephron
.
Am. J. Physiol. Renal Physiol.
284
,
F812
F828
[PubMed]
52
Frindt
G.
and
Palmer
L.G.
(
2004
)
Apical potassium channels in the rat connecting tubule
.
Am. J. Physiol. Renal Physiol.
287
,
F1030
F1037
[PubMed]
53
Hunter
M.
,
Lopes
A.G.
,
Boulpaep
E.L.
and
Giebisch
G.H.
(
1984
)
Single channel recordings of calcium-activated potassium channels in the apical membrane of rabbit cortical collecting tubules
.
Proc. Natl. Acad. Sci. USA
81
,
4237
4239
54
Pacha
J.
,
Frindt
G.
,
Sackin
H.
and
Palmer
L.G.
(
1991
)
Apical maxi K channels in intercalated cells of CCT
.
Am. J. Physiol.
261
,
F696
F705
[PubMed]
55
Grimm
P.R.
,
Foutz
R.M.
,
Brenner
R.
and
Sansom
S.C.
(
2007
)
Identification and localization of BK-beta subunits in the distal nephron of the mouse kidney
.
Am. J. Physiol. Renal Physiol.
293
,
F350
F359
[PubMed]
56
Pluznick
J.L.
,
Wei
P.
,
Grimm
P.R.
and
Sansom
S.C.
(
2005
)
BK-{beta}1 subunit: immunolocalization in the mammalian connecting tubule and its role in the kaliuretic response to volume expansion
.
Am. J. Physiol. Renal Physiol.
288
,
F846
F854
[PubMed]
57
Taniguchi
J.
and
Imai
M.
(
1998
)
Flow-dependent activation of maxi K+ channels in apical membrane of rabbit connecting tubule
.
J. Membr. Biol.
164
,
35
45
[PubMed]
58
Najjar
F.
,
Zhou
H.
,
Morimoto
T.
,
Bruns
J.B.
,
Li
H.S.
,
Liu
W.
et al. 
(
2005
)
Dietary K+ regulates apical membrane expression of maxi-K channels in rabbit cortical collecting duct
.
Am. J. Physiol. Renal Physiol.
289
,
F922
F932
[PubMed]
59
Bailey
M.A.
,
Cantone
A.
,
Yan
Q.
,
MacGregor
G.G.
,
Leng
Q.
,
Amorim
J.B.
et al. 
(
2006
)
Maxi-K channels contribute to urinary potassium excretion in the ROMK-deficient mouse model of Type II Bartter's syndrome and in adaptation to a high-K diet
.
Kidney Int.
70
,
51
59
[PubMed]
60
Estilo
G.
,
Liu
W.
,
Pastor-Soler
N.
,
Mitchell
P.
,
Carattino
M.D.
,
Kleyman
T.R.
et al. 
(
2008
)
Effect of aldosterone on BK channel expression in mammalian cortical collecting duct
.
Am. J. Physiol. Renal Physiol.
295
,
F780
F788
[PubMed]
61
Taniguchi
J.
and
Guggino
W.B.
(
1989
)
Membrane stretch: a physiological stimulator of Ca2+-activated K+ channels in thick ascending limb
.
Am. J. Physiol.
257
,
F347
F352
[PubMed]
62
Sorensen
M.V.
,
Matos
J.E.
,
Sausbier
M.
,
Sausbier
U.
,
Ruth
P.
,
Praetorius
H.A.
et al. 
(
2008
)
Aldosterone increases KCa1.1 (BK) channel-mediated colonic K+ secretion
.
J. Physiol.
586
,
4251
4264
[PubMed]
63
Wen
D.
,
Cornelius
R.J.
,
Yuan
Y.
and
Sansom
S.C.
(
2013
)
Regulation of BK-alpha expression in the distal nephron by aldosterone and urine pH
.
Am. J. Physiol. Renal Physiol.
305
,
F463
F476
[PubMed]
64
Cornelius
R.J.
,
Wen
D.
,
Li
H.
,
Yuan
Y.
,
Wang-France
J.
,
Warner
P.C.
et al. 
(
2015
)
Low Na, high K diet and the role of aldosterone in BK-mediated K excretion
.
PLoS One
10
,
e0115515
[PubMed]
65
Yang
L.
,
Frindt
G.
,
Lang
F.
,
Kuhl
D.
,
Vallon
V.
and
Palmer
L.G.
(
2017
)
SGK1-dependent ENaC processing and trafficking in mice with high dietary K intake and elevated aldosterone
.
Am. J. Physiol. Renal Physiol.
312
,
F65
F76
[PubMed]
66
Hoenderop
J.G.
,
van der Kemp
A.W.
,
Hartog
A.
,
van de Graaf
S.F.
,
van Os
C.H.
,
Willems
P.H.
et al. 
(
1999
)
Molecular identification of the apical Ca2+ channel in 1, 25-dihydroxyvitamin D3-responsive epithelia
.
J. Biol. Chem.
274
,
8375
8378
[PubMed]
67
Hoenderop
J.G.
,
Vennekens
R.
,
Muller
D.
,
Prenen
J.
,
Droogmans
G.
,
Bindels
R.J.
et al. 
(
2001
)
Function and expression of the epithelial Ca(2+) channel family: comparison of mammalian ECaC1 and 2
.
J. Physiol.
537
,
747
761
[PubMed]
68
Vennekens
R.
,
Hoenderop
J.G.
,
Prenen
J.
,
Stuiver
M.
,
Willems
P.H.
,
Droogmans
G.
et al. 
(
2000
)
Permeation and gating properties of the novel epithelial Ca(2+) channel
.
J. Biol. Chem.
275
,
3963
3969
[PubMed]
69
Nijenhuis
T.
,
Hoenderop
J.G.
,
van der Kemp
A.W.
and
Bindels
R.J.
(
2003
)
Localization and regulation of the epithelial Ca2+ channel TRPV6 in the kidney
.
J. Am. Soc. Nephrol.
14
,
2731
2740
[PubMed]
70
Palmada
M.
,
Poppendieck
S.
,
Embark
H.M.
,
van de Graaf
S.F.
,
Boehmer
C.
,
Bindels
R.J.
et al. 
(
2005
)
Requirement of PDZ domains for the stimulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase SGK1
.
Cell. Physiol. Biochem.
15
,
175
182
[PubMed]
71
Embark
H.M.
,
Setiawan
I.
,
Poppendieck
S.
,
van de Graaf
S.F.
,
Boehmer
C.
,
Palmada
M.
et al. 
(
2004
)
Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes
.
Cell. Physiol. Biochem.
14
,
203
212
[PubMed]
72
Bohmer
C.
,
Palmada
M.
,
Kenngott
C.
,
Lindner
R.
,
Klaus
F.
,
Laufer
J.
et al. 
(
2007
)
Regulation of the epithelial calcium channel TRPV6 by the serum and glucocorticoid-inducible kinase isoforms SGK1 and SGK3
.
FEBS Lett.
581
,
5586
5590
[PubMed]
73
Voets
T.
,
Prenen
J.
,
Vriens
J.
,
Watanabe
H.
,
Janssens
A.
,
Wissenbach
U.
et al. 
(
2002
)
Molecular determinants of permeation through the cation channel TRPV4
.
J. Biol. Chem.
277
,
33704
33710
[PubMed]
74
Watanabe
H.
,
Vriens
J.
,
Janssens
A.
,
Wondergem
R.
,
Droogmans
G.
and
Nilius
B.
(
2003
)
Modulation of TRPV4 gating by intra- and extracellular Ca2+
.
Cell Calcium
33
,
489
495
[PubMed]
75
Berrout
J.
,
Jin
M.
,
Mamenko
M.
,
Zaika
O.
,
Pochynyuk
O.
and
O'Neil
R.G.
(
2012
)
Function of transient receptor potential cation channel subfamily V member 4 (TRPV4) as a mechanical transducer in flow-sensitive segments of renal collecting duct system
.
J. Biol. Chem.
287
,
8782
8791
[PubMed]
76
Strotmann
R.
,
Harteneck
C.
,
Nunnenmacher
K.
,
Schultz
G.
and
Plant
T.D.
(
2000
)
OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity
.
Nat. Cell Biol.
2
,
695
702
[PubMed]
77
Liedtke
W.
,
Choe
Y.
,
Marti-Renom
M.A.
,
Bell
A.M.
,
Denis
C.S.
,
Sali
A.
et al. 
(
2000
)
Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor
.
Cell
103
,
525
535
[PubMed]
78
Wu
L.
,
Gao
X.
,
Brown
R.C.
,
Heller
S.
and
O'Neil
R.G.
(
2007
)
Dual role of the TRPV4 channel as a sensor of flow and osmolality in renal epithelial cells
.
Am. J. Physiol. Renal Physiol.
293
,
F1699
F1713
[PubMed]
79
Gao
X.
,
Wu
L.
and
O'Neil
R.G.
(
2003
)
Temperature-modulated diversity of TRPV4 channel gating: activation by physical stresses and phorbol ester derivatives through protein kinase C-dependent and -independent pathways
.
J. Biol. Chem.
278
,
27129
27137
[PubMed]
80
Mendoza
S.A.
,
Fang
J.
,
Gutterman
D.D.
,
Wilcox
D.A.
,
Bubolz
A.H.
,
Li
R.
et al. 
(
2010
)
TRPV4-mediated endothelial Ca2+ influx and vasodilation in response to shear stress
.
Am. J. Physiol. Heart Circ. Physiol.
298
,
H466
H476
[PubMed]
81
Hartmannsgruber
V.
,
Heyken
W.T.
,
Kacik
M.
,
Kaistha
A.
,
Grgic
I.
,
Harteneck
C.
et al. 
(
2007
)
Arterial response to shear stress critically depends on endothelial TRPV4 expression
.
PLoS One
2
,
e827
[PubMed]
82
Suzuki
M.
,
Mizuno
A.
,
Kodaira
K.
and
Imai
M.
(
2003
)
Impaired pressure sensation in mice lacking TRPV4
.
J. Biol. Chem.
278
,
22664
22668
[PubMed]
83
Taniguchi
J.
,
Tsuruoka
S.
,
Mizuno
A.
,
Sato
J.
,
Fujimura
A.
and
Suzuki
M.
(
2007
)
TRPV4 as a flow sensor in flow-dependent K+ secretion from the cortical collecting duct
.
Am. J. Physiol. Renal Physiol.
292
,
F667
F673
[PubMed]
84
Mamenko
M.V.
,
Boukelmoune
N.
,
Tomilin
V.N.
,
Zaika
O.L.
,
Jensen
V.B.
,
O'Neil
R.G.
et al. 
(
2017
)
The renal TRPV4 channel is essential for adaptation to increased dietary potassium
.
Kidney Int.
91
,
1398
1409
[PubMed]
85
Laragh
J.H.
and
Stoerk
H.C.
(
1957
)
A study of the mechanism of secretion of the sodium-retaining hormone (aldosterone)
.
J. Clin. Invest.
36
,
383
392
[PubMed]
86
Shin
S.H.
,
Lee
E.J.
,
Hyun
S.
,
Chun
J.
,
Kim
Y.
and
Kang
S.S.
(
2012
)
Phosphorylation on the Ser 824 residue of TRPV4 prefers to bind with F-actin than with microtubules to expand the cell surface area
.
Cell Signal.
24
,
641
651
[PubMed]
87
Schlingmann
K.P.
,
Weber
S.
,
Peters
M.
,
Niemann Nejsum
L.
,
Vitzthum
H.
,
Klingel
K.
et al. 
(
2002
)
Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family
.
Nat. Genet.
31
,
166
170
[PubMed]
88
Voets
T.
,
Nilius
B.
,
Hoefs
S.
,
van der Kemp
A.W.
,
Droogmans
G.
,
Bindels
R.J.
et al. 
(
2004
)
TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption
.
J. Biol. Chem.
279
,
19
25
[PubMed]
89
Valinsky
W.C.
,
Touyz
R.M.
and
Shrier
A.
(
2017
)
Characterization of constitutive and acid-induced outwardly rectifying chloride currents in immortalized mouse distal tubular cells
.
Biochim. Biophys. Acta
1861
,
2007
2019
[PubMed]
90
Ledeganck
K.J.
,
Boulet
G.A.
,
Horvath
C.A.
,
Vinckx
M.
,
Bogers
J.J.
,
Van Den Bossche
R.
et al. 
(
2011
)
Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment
.
Am. J. Physiol. Renal Physiol.
301
,
F486
F493
[PubMed]
91
Runnels
L.W.
,
Yue
L.
and
Clapham
D.E.
(
2001
)
TRP-PLIK, a bifunctional protein with kinase and ion channel activities
.
Science
291
,
1043
1047
[PubMed]
92
Goytain
A.
and
Quamme
G.A.
(
2005
)
Identification and characterization of a novel mammalian Mg2+ transporter with channel-like properties
.
BMC Genomics
6
,
48
[PubMed]
93
Zhou
H.
and
Clapham
D.E.
(
2009
)
Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development
.
Proc. Natl. Acad. Sci. USA
106
,
15750
15755
94
Goytain
A.
and
Quamme
G.A.
(
2005
)
Functional characterization of ACDP2 (ancient conserved domain protein), a divalent metal transporter
.
Physiol. Genomics
22
,
382
389
[PubMed]
95
Riazanova
L.V.
,
Pavur
K.S.
,
Petrov
A.N.
,
Dorovkov
M.V.
and
Riazanov
A.G.
(
2001
)
Novel type of signaling molecules: protein kinases covalently linked to ion channels
.
Mol. Biol. (Mosk)
35
,
321
332
[PubMed]
96
Nadler
M.J.
,
Hermosura
M.C.
,
Inabe
K.
,
Perraud
A.L.
,
Zhu
Q.
,
Stokes
A.J.
et al. 
(
2001
)
LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability
.
Nature
411
,
590
595
[PubMed]
97
Yamauchi
T.
,
Kamon
J.
,
Waki
H.
,
Murakami
K.
,
Motojima
K.
,
Komeda
K.
et al. 
(
2001
)
The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance
.
J. Biol. Chem.
276
,
41245
41254
[PubMed]
98
Ryazanova
L.V.
,
Dorovkov
M.V.
,
Ansari
A.
and
Ryazanov
A.G.
(
2004
)
Characterization of the protein kinase activity of TRPM7/ChaK1, a protein kinase fused to the transient receptor potential ion channel
.
J. Biol. Chem.
279
,
3708
3716
[PubMed]
99
Krapivinsky
G.
,
Krapivinsky
L.
,
Manasian
Y.
and
Clapham
D.E.
(
2014
)
The TRPM7 chanzyme is cleaved to release a chromatin-modifying kinase
.
Cell
157
,
1061
1072
[PubMed]
100
Krapivinsky
G.
,
Krapivinsky
L.
,
Renthal
N.E.
,
Santa-Cruz
A.
,
Manasian
Y.
and
Clapham
D.E.
(
2017
)
Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression
.
Proc. Natl. Acad. Sci. USA
114
,
E7092
E7100
101
Yogi
A.
,
Callera
G.E.
,
O'Connor
S.E.
,
He
Y.
,
Correa
J.W.
,
Tostes
R.C.
et al. 
(
2011
)
Dysregulation of renal transient receptor potential melastatin 6/7 but not paracellin-1 in aldosterone-induced hypertension and kidney damage in a model of hereditary hypomagnesemia
.
J. Hypertens.
29
,
1400
1410
[PubMed]
102
Yogi
A.
,
Callera
G.E.
,
O'Connor
S.
,
Antunes
T.T.
,
Valinsky
W.
,
Miquel
P.
et al. 
(
2013
)
Aldosterone signaling through transient receptor potential melastatin 7 cation channel (TRPM7) and its alpha-kinase domain
.
Cell Signal.
25
,
2163
2175
[PubMed]
103
Valinsky
W.C.
,
Jolly
A.
,
Miquel
P.
,
Touyz
R.M.
and
Shrier
A.
(
2016
)
Aldosterone upregulates transient receptor potential melastatin 7 (TRPM7)
.
J. Biol. Chem.
,
291
,
20163
20172
104
Jiang
J.
,
Li
M.
and
Yue
L.
(
2005
)
Potentiation of TRPM7 inward currents by protons
.
J. Gen. Physiol.
126
,
137
150
[PubMed]
105
Li
M.
,
Du
J.
,
Jiang
J.
,
Ratzan
W.
,
Su
L.T.
,
Runnels
L.W.
et al. 
(
2007
)
Molecular determinants of Mg2+ and Ca2+ permeability and pH sensitivity in TRPM6 and TRPM7
.
J. Biol. Chem.
282
,
25817
25830
[PubMed]
106
Monteilh-Zoller
M.K.
,
Hermosura
M.C.
,
Nadler
M.J.
,
Scharenberg
A.M.
,
Penner
R.
and
Fleig
A.
(
2003
)
TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions
.
J. Gen. Physiol.
121
,
49
60
[PubMed]
107
Li
M.
,
Jiang
J.
and
Yue
L.
(
2006
)
Functional characterization of homo- and heteromeric channel kinases TRPM6 and TRPM7
.
J. Gen. Physiol.
127
,
525
537
[PubMed]
108
Ryazanova
L.V.
,
Rondon
L.J.
,
Zierler
S.
,
Hu
Z.
,
Galli
J.
,
Yamaguchi
T.P.
et al. 
(
2010
)
TRPM7 is essential for Mg(2+) homeostasis in mammals
.
Nat. Commun.
1
,
109
[PubMed]
109
Chubanov
V.
,
Ferioli
S.
,
Wisnowsky
A.
,
Simmons
D.G.
,
Leitzinger
C.
,
Einer
C.
et al. 
(
2016
)
Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival
.
Elife
5
,
e20914
[PubMed]
110
Uchida
S.
,
Sasaki
S.
,
Furukawa
T.
,
Hiraoka
M.
,
Imai
T.
,
Hirata
Y.
et al. 
(
1993
)
Molecular cloning of a chloride channel that is regulated by dehydration and expressed predominantly in kidney medulla
.
J. Biol. Chem.
268
,
3821
3824
[PubMed]
111
Vandewalle
A.
,
Cluzeaud
F.
,
Bens
M.
,
Kieferle
S.
,
Steinmeyer
K.
and
Jentsch
T.J.
(
1997
)
Localization and induction by dehydration of ClC-K chloride channels in the rat kidney
.
Am. J. Physiol.
272
,
F678
F688
[PubMed]
112
Embark
H.M.
,
Bohmer
C.
,
Palmada
M.
,
Rajamanickam
J.
,
Wyatt
A.W.
,
Wallisch
S.
et al. 
(
2004
)
Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases
.
Kidney Int.
66
,
1918
1925
[PubMed]
113
Kobayashi
K.
,
Uchida
S.
,
Mizutani
S.
,
Sasaki
S.
and
Marumo
F.
(
2001
)
Intrarenal and cellular localization of CLC-K2 protein in the mouse kidney
.
J. Am. Soc. Nephrol.
12
,
1327
1334
[PubMed]
114
Uchida
S.
,
Sasaki
S.
,
Nitta
K.
,
Uchida
K.
,
Horita
S.
,
Nihei
H.
et al. 
(
1995
)
Localization and functional characterization of rat kidney-specific chloride channel, ClC-K1
.
J. Clin. Invest.
95
,
104
113
[PubMed]
115
Kieferle
S.
,
Fong
P.
,
Bens
M.
,
Vandewalle
A.
and
Jentsch
T.J.
(
1994
)
Two highly homologous members of the ClC chloride channel family in both rat and human kidney
.
Proc. Natl. Acad. Sci. USA
91
,
6943
6947
116
Rubera
I.
,
Tauc
M.
,
Verheecke-Mauze
C.
,
Bidet
M.
,
Poujeol
C.
,
Touret
N.
et al. 
(
1999
)
Regulation of cAMP-dependent chloride channels in DC1 immortalized rabbit distal tubule cells in culture
.
Am. J. Physiol.
276
,
F104
F121
[PubMed]
117
Tauc
M.
,
Bidet
M.
and
Poujeol
P.
(
1996
)
Chloride currents activated by calcitonin and cAMP in primary cultures of rabbit distal convoluted tubule
.
J. Membr. Biol.
150
,
255
273
[PubMed]
118
Caohuy
H.
,
Jozwik
C.
and
Pollard
H.B.
(
2009
)
Rescue of DeltaF508-CFTR by the SGK1/Nedd4-2 signaling pathway
.
J. Biol. Chem.
284
,
25241
25253
[PubMed]
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