Kir4.1/Kir5.1 channel forms the major K<sup>+</sup>channel in the basolateral membrane of mouse renal collecting duct principal cells

Lachheb, Sahran; Cluzeaud, Françoise; Bens, Marcelle; Genête, Mathieu; Hibino, Hiroshi; Lourdel, Stéphane; Kurachi, Yoshihisa; Vandewalle, Alain; Teulon, Jacques; Paulais, Marc

doi:10.1152/ajprenal.00288.2007

Cited by 110 publications

(110 citation statements)

References 49 publications

(67 reference statements)

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“…8,9 This 40 pS K + channel is a heterotetramer of Kir4.1 and Kir5.1 because the coexpression of Kir4.1/5.1 produced an inwardly rectifying K + channel with the same biophysical properties as the 40 pS K + channel expressed in the basolateral membrane of the native DCT. [10][11][12] The role of Kir4.1 in forming the basolateral 40 pS K + channel of the DCT was convincingly demonstrated by the observation that the disruption of Kcnj10 (Kir.4.1) completely eliminated the 40 pS K + channel. 13 Moreover, the basolateral K + conductance was largely abolished in the early DCT (DCT1) of Kcnj10 2/2 mice, suggesting that Kcnj10 (Kir.4.1) is a major contributor to the basolateral K + conductance in the DCT1.…”

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confidence: 94%

Caveolin-1 Deficiency Inhibits the Basolateral K+ Channels in the Distal Convoluted Tubule and Impairs Renal K+ and Mg2+ Transport

Wang

Zhang

et al. 2015

Journal of the American Society of Nephrology

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Kir4.1/Kir5.1, in the basolateral membrane of the early DCT (DCT1) in both wild-type (WT) and cav-1-knockout (KO) mice. However, the activity of this basolateral 40-pS K + channel was lower in KO mice than in WT mice. Moreover, the K + reversal potential (an indication of membrane potential) was less negative in the DCT1 of KO mice than in the DCT1 of WT mice. Western blot analysis demonstrated that cav-1 deficiency decreased the expression of the Na + /Cl -cotransporter and Ste20-proline-alanine-rich kinase (SPAK) but increased the expression of epithelial Na + channel-a. Furthermore, the urinary excretion of Mg 2+ and K + was significantly higher in KO mice than in WT mice, and KO mice developed hypomagnesemia, hypocalcemia, and hypokalemia. We conclude that disruption of cav-1 decreases basolateral K + channel activity and depolarizes the cell membrane potential in the DCT1 at least in part by suppressing the stimulatory effect of c-Src on Kcnj10. Furthermore, the decrease in Kcnj10 and Na + /Cl -cotransporter expression induced by cav-1 deficiency may underlie the compromised renal transport of Mg 2+ , Ca 2+ , and K + .

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confidence: 94%

Caveolin-1 Deficiency Inhibits the Basolateral K+ Channels in the Distal Convoluted Tubule and Impairs Renal K+ and Mg2+ Transport

Wang

Zhang

et al. 2015

Journal of the American Society of Nephrology

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“…However, they could offer some important advantages over conventional diuretics due to the localization of the channel on the basolateral membrane. [10][11][12] Loop and thiazide diuretics must first be secreted by renal proximal tubule cells before reaching their sites of action on the apical membrane. [13][14][15][16] Interactions between diuretics and other secreted drugs, including antibiotics, NSAIDs, antivirals, as well as organic acid in the setting of renal failure, can limit their secretion and natriuretic effects.…”

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confidence: 99%

Development and Validation of Fluorescence-Based and Automated Patch Clamp–Based Functional Assays for the Inward Rectifier Potassium Channel Kir4.1

RaphemotRene

KadakiaRishin

Olsen

et al. 2013

ASSAY and Drug Development Technologies

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The inward rectifier potassium (Kir) channel Kir4.1 plays essential roles in modulation of neurotransmission and renal sodium transport and may represent a novel drug target for temporal lobe epilepsy and hypertension. The molecular pharmacology of Kir4.1 is limited to neurological drugs, such as fluoxetine (Prozac ª ), exhibiting weak and nonspecific activity toward the channel. The development of potent and selective small-molecule probes would provide critically needed tools for exploring the integrative physiology and therapeutic potential of Kir4.1. A fluorescence-based thallium (Tl + ) flux assay that utilizes a tetracycline-inducible T-Rex-HEK293-Kir4.1 cell line to enable high-throughput screening (HTS) of small-molecule libraries was developed. The assay is dimethyl sulfoxide tolerant and exhibits robust screening statistics (Z 0 = 0.75 -0.06). A pilot screen of 3,655 small molecules and lipids revealed 16 Kir4.1 inhibitors (0.4% hit rate). 3,3-Diphenyl-N-(1-phenylethyl)propan-1-amine, termed VU717, inhibits Kir4.1-mediated thallium flux with an IC 50 of *6 lM. An automated patch clamp assay using the IonFlux HT workbench was developed to facilitate compound characterization. Leak-subtracted ensemble ''loose patch'' recordings revealed robust tetracycline-inducible and Kir4.1 currents that were inhibited by fluoxetine (IC 50 = 10 lM), VU717 (IC 50 = 6 lM), and structurally related calcium channel blocker prenylamine (IC 50 = 6 lM). Finally, we demonstrate that VU717 inhibits Kir4.1 channel activity in cultured rat astrocytes, providing proof-of-concept that the Tl + flux and IonFlux HT assays can enable the discovery of antagonists that are active against native Kir4.1 channels.

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“…Kir4.1 channel is found in the kidney, retina, and central nervous system as a homodimeric or heterodimeric (together with the Kir5.1) channel, acting as a K + transporter or a pHdependent membrane potential regulator (50,62). Jin et al has found that the presence of Kir5.1 in the Kir4-Kir5 heterodimeric channel enables channel sensitivity to Sglutathionylation.…”

Section: S-glutathionylation Of Kir4-kir5 Channelmentioning

confidence: 99%

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

Yang

Jin²,

Jiang³

2014

Antioxidants & Redox Signaling

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Significance: Ion channels control membrane potential, cellular excitability, and Ca ++ signaling, all of which play essential roles in cellular functions. The regulation of ion channels enables cells to respond to changing environments, and post-translational modification (PTM) is one major regulation mechanism. Recent Advances: Many PTMs (e.g., S-glutathionylation, S-nitrosylation, S-palmitoylation, S-sulfhydration, etc.) targeting the thiol group of cysteine residues have emerged to be essential for ion channels regulation under physiological and pathological conditions. Critical Issues: Under oxidative stress, S-glutathionylation could be a critical PTM that regulates many molecules. In this review, we discuss S-glutathionylation-mediated structural and functional changes of ion channels. Criteria for testing S-glutathionylation, methods and reagents used in ion channel S-glutathionylation studies, and thiol modification crosstalk, are also covered. Mechanotransduction, and S-glutathionylation of the mechanosensitive K ATP channel, are discussed. Future Directions: Further investigation of the ion channel S-glutathionylation, especially the physiological significance of S-glutathionylation and thiol modification crosstalk, could lead to a better understanding of the thiol modifications in general and the ramifications of such modifications on cellular functions and related diseases. Antioxid. Redox Signal. 20, 937-951.

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Kir4.1/Kir5.1 channel forms the major K⁺channel in the basolateral membrane of mouse renal collecting duct principal cells

Cited by 110 publications

References 49 publications

Caveolin-1 Deficiency Inhibits the Basolateral K+ Channels in the Distal Convoluted Tubule and Impairs Renal K+ and Mg2+ Transport

Caveolin-1 Deficiency Inhibits the Basolateral K+ Channels in the Distal Convoluted Tubule and Impairs Renal K+ and Mg2+ Transport

Development and Validation of Fluorescence-Based and Automated Patch Clamp–Based Functional Assays for the Inward Rectifier Potassium Channel Kir4.1

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

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Kir4.1/Kir5.1 channel forms the major K+channel in the basolateral membrane of mouse renal collecting duct principal cells

Cited by 110 publications

References 49 publications

Caveolin-1 Deficiency Inhibits the Basolateral K+ Channels in the Distal Convoluted Tubule and Impairs Renal K+ and Mg2+ Transport

Caveolin-1 Deficiency Inhibits the Basolateral K+ Channels in the Distal Convoluted Tubule and Impairs Renal K+ and Mg2+ Transport

Development and Validation of Fluorescence-Based and Automated Patch Clamp–Based Functional Assays for the Inward Rectifier Potassium Channel Kir4.1

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

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Kir4.1/Kir5.1 channel forms the major K⁺channel in the basolateral membrane of mouse renal collecting duct principal cells