Physiological roles of CLC Cl−/H+ exchangers in renal proximal tubules

Plans, Vanessa; Rickheit, Gesa; Jentsch, Thomas J.

doi:10.1007/s00424-008-0597-z

Cited by 33 publications

(25 citation statements)

References 120 publications

(246 reference statements)

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“…(Lloyd et al, 1996;Pook et al, 1993). The underlying defect was identified as an inability of the tubule cells to perform megalin-mediated uptake of vitamin D metabolites bound to DBP (Plans et al, 2009). The same finding was obtained in mouse models of ClC-5 deficiency (Piwon et al, 2000;Wang et al, 2000).…”

Section: Megalin a Receptor For Cellular Uptake Of Vitamin D Metabolmentioning

confidence: 99%

Cellular uptake of steroid carrier proteins—Mechanisms and implications

Willnow

Nykjaer

2010

Molecular and Cellular Endocrinology

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Steroid hormones are believed to enter cells solely by free diffusion through the plasma membrane. However, recent studies suggest the existence of cellular uptake pathways for carrier-bound steroids. Similar to the clearance of cholesterol via lipoproteins, these pathways involve the recognition of carrier proteins by endocytic receptors on the surface of target cells, followed by internalization and cellular delivery of the bound sterols. Here, we discuss the emerging concept that steroid hormones can selectively enter steroidogenic tissues by receptor-mediated endocytosis; and we discuss the implications of these uptake pathways for steroid hormone metabolism and action in vivo.

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Section: Megalin a Receptor For Cellular Uptake Of Vitamin D Metabolmentioning

confidence: 99%

Cellular uptake of steroid carrier proteins—Mechanisms and implications

Willnow

Nykjaer

2010

Molecular and Cellular Endocrinology

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“…As noted in the Introduction, SERCA acts as an antiporter: two Ca 2+ ions pumped into the ER lumen for two to three protons from the lumen released into the cytoplasm (Levy et al, 1990). In addition, the influx of Cl -counterions through ClC leads to proton extrusion from the ER lumen (Jentsch, 2007;Picollo and Pusch, 2005;Plans et al, 2009;Scheel et al, 2005). Without proton re-entry, the ER lumen would be alkalinized, thus blocking further the activity of SERCA.…”

Section: Discussionmentioning

confidence: 99%

“…Chloride-channel (ClC)-type proteins are present in the ER and colocalize with SERCA. Recent evidence suggests also that intracellular ClC3-7 proteins are exchangers rather than channels (Jentsch, 2007;Picollo and Pusch, 2005;Plans et al, 2009;Scheel et al, 2005). The stoichiometry of ion exchange is thought to be approximately 2 Cl -for 1 H + for ClC4, 5 and 7 (Graves et al, 2008;Picollo and Pusch, 2005;Scheel et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum potassium–hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes

Kuum

Veksler

Liiv

et al. 2012

Journal of Cell Science

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SummaryCalcium pumping into the endoplasmic reticulum (ER) lumen is thought to be coupled to a countertransport of protons through sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) and the members of the ClC family of chloride channels. However, pH in the ER lumen remains neutral, which suggests a mechanism responsible for proton re-entry. We studied whether cation-proton exchangers could act as routes for such a re-entry. ER Ca 2+ uptake was measured in permeabilized immortalized hypothalamic neurons, primary rat cortical neurons and mouse cardiac fibers. Replacement of K + in the uptake solution with Na + or tetraethylammonium led to a strong inhibition of Ca 2+ uptake in neurons and cardiomyocytes. Furthermore, inhibitors of the potassium-proton exchanger (quinine or propranolol) but not of the sodium-proton exchanger reduced ER Ca 2+ uptake by 56-82%. Externally added nigericin, a potassiumproton exchanger, attenuated the inhibitory effect of propranolol. Inhibitors of small conductance calcium-sensitive K + (SK Ca ) channels (UCL 1684, dequalinium) blocked the uptake of Ca 2+ by the ER in all preparations by 48-94%, whereas inhibitors of other K + channels (IK Ca , BK Ca and K ATP ) had no effect. Fluorescence microscopy and western blot analysis revealed the presence of both SK Ca channels and the potassium-proton exchanger leucine zipper-EF-hand-containing transmembrane protein 1 (LETM1) in ER in situ and in the purified ER fraction. The data obtained demonstrate that SK Ca channels and LETM1 reside in the ER membrane and that their activity is essential for ER Ca 2+ uptake.

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“…About half of all CLCs are secondary active transporters, catalyzing the stoichiometric exchange of two Cl Ϫ ions for one proton, while the other half are passive channels, catalyzing rapid downhill movement of Cl Ϫ (1, 109, 120). Both types play important roles in kidney tubular function (23,26,30,86,88,110,151). In the channel branch of the family, the two kidney-specific homologs, ClC-Ka and ClCKb, have central roles in tubular Cl Ϫ reabsorption that make them important targets for novel therapeutic interventions (36,41,61,63,65,75).…”

Section: Clc-ka/bmentioning

confidence: 99%

Novel diuretic targets

Denton

Pao

Maduke

2013

American Journal of Physiology-Renal Physiology

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As the molecular revolution continues to inform a deeper understanding of disease mechanisms and pathways, there exist unprecedented opportunities for translating discoveries at the bench into novel therapies for improving human health. Despite the availability of several different classes of antihypertensive medications, only about half of the 67 million Americans with hypertension manage their blood pressure appropriately. A broader selection of structurally diverse antihypertensive drugs acting through different mechanisms would provide clinicians with greater flexibility in developing effective treatment regimens for an increasingly diverse and aging patient population. An emerging body of physiological, genetic, and pharmacological evidence has implicated several renal ion-transport proteins, or regulators thereof, as novel, yet clinically unexploited, diuretic targets. These include the renal outer medullary potassium channel, ROMK (Kir1.1), Kir4.1/5.1 potassium channels, ClC-Ka/b chloride channels, UTA/B urea transporters, the chloride/bicarbonate exchanger pendrin, and the STE20/SPS1-related proline/alanine-rich kinase (SPAK). The molecular pharmacology of these putative targets is poorly developed or lacking altogether; however, recent efforts by a few academic and pharmaceutical laboratories have begun to lessen this critical barrier. Here, we review the evidence in support of the aforementioned proteins as novel diuretic targets and highlight examples where progress toward developing small-molecule pharmacology has been made.

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Physiological roles of CLC Cl−/H+ exchangers in renal proximal tubules

Cited by 33 publications

References 120 publications

Cellular uptake of steroid carrier proteins—Mechanisms and implications

Cellular uptake of steroid carrier proteins—Mechanisms and implications

Endoplasmic reticulum potassium–hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes

Novel diuretic targets

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