Upregulation of KCNQ1/KCNE1 K+channels by Klotho

Almilaji, Ahmad; Pakladok, Tatsiana; Muñoz, Carlos; Elvira, Bernat; Sopjani, Mentor; Läng, Florian

doi:10.4161/chan.27662

Cited by 13 publications

(10 citation statements)

References 69 publications

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“…Klotho deficiency is followed by excessive 1,25(OH) 2 D 3 formation [2,13,14] leading to increase of plasma Ca 2+ [18] and phosphate [17] concentrations as well as vascular calcification [19]. Besides its effect on 1,25(OH) 2 D 3 formation, klotho modifies the function of several transport proteins including Ca 2+ channels [20], Na + ,phosphate cotransport [4,21], Na + /K + ATPase [22], renal outer medullary K + channels [23], Kv1.3 K + channels [24], KCNQ1/KCNE1 [25], the creatine transporter CreaT [26], and the excitatory amino acid transporters EAAT1, EAAT2, EAAT3 and EAAT4 [27,28].…”

Section: Introductionmentioning

confidence: 99%

β-Klotho as a Negative Regulator of the Peptide Transporters PEPT1 and PEPT2

Abousaab

Warsi²,

Salker³

et al. 2016

Cell Physiol Biochem

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Background/Aims: β-Klotho, a transmembrane protein expressed in several tissues including the brain and the kidney, is critically important for inhibition of 1,25(OH)₂D₃ formation by FGF23. The extracellular domain of Klotho protein could be cleaved off, thus being released into blood or cerebrospinal fluid. Soluble klotho is a β-glucuronidase participating in the regulation of several ion channels and carriers. The present study explored the effect of β-Klotho protein on the peptide transporters PEPT1 and PEPT2. Methods: cRNA encoding PEPT1 or PEPT2 was injected into Xenopus laevis oocytes and glycine-glycine (2 mM)-induced inward current (I_Gly) taken as measure of glycine-glycine transport. Measurements were made without or with prior 24 h treatment with soluble β-Klotho protein (30 ng/ml) in the absence and presence of β-glucuronidase inhibitor D-saccharic acid 1,4-lactone monohydrate (DSAL,10 µM). Ussing chamber experiments were employed to determine electrogenic peptide transport across intestinal epithelia of klotho deficient (kl^-/-) and corresponding wild type (kl^+/+) mice. Results: I_Gly was observed in PEPT1 and in PEPT2 expressing oocytes but not in water injected oocytes. In both, PEPT1 and PEPT2 expressing oocytes I_Gly was significantly decreased by treatment with soluble β-Klotho protein. As shown for PEPT1, β-klotho protein decreased significantly the maximal transport rate without significantly modifying the affinity of the carrier. The effect of β-Klotho on PEPT1 was reversed by DSAL. Intestinal I_Gly was significantly larger in kl^-/- than in kl^+/+ mice. Conclusion: β-Klotho participates in the regulation of the peptide transporters PEPT1 and PEPT2.

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Section: Introductionmentioning

confidence: 99%

β-Klotho as a Negative Regulator of the Peptide Transporters PEPT1 and PEPT2

Abousaab

Warsi²,

Salker³

et al. 2016

Cell Physiol Biochem

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“…Klotho has previously been shown to affect a variety of further channels, such as the epithelial Ca 2+ channels TRPV5 [62,63,64,65,66] and TRPV6 [66], as well as the K + channels ROMK [24,62], KCNQ1/KCNE1 [67] and hERG [68]. Klotho apparently does not appreciably affect the channels TRPV4 [66] or TRPM6 [66].…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Voltage Gated K+ Channel Kv1.3 by Recombinant Human Klotho Protein

Almilaji

Honisch

Liu

et al. 2014

Kidney Blood Press Res

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Background/Aims: Klotho, a protein mainly produced in the kidney and released into circulating blood, contributes to the negative regulation of 1,25(OH)₂D₃ formation and is thus a powerful regulator of mineral metabolism. As β-glucuronidase, alpha Klotho protein further regulates the stability of several carriers and channels in the plasma membrane and thus regulates channel and transporter activity. Accordingly, alpha Klotho protein participates in the regulation of diverse functions seemingly unrelated to mineral metabolism including lymphocyte function. The present study explored the impact of alpha Klotho protein on the voltage gated K⁺ channel K_v1.3. Methods: cRNA encoding K_v1.3 (KCNA3) was injected into Xenopus oocytes and depolarization induced outward current in K_v1.3 expressing Xenopus oocytes determined utilizing dual electrode voltage clamp. Experiments were performed without or with prior treatment with recombinant human Klotho protein (50 ng/ml, 24 hours) in the absence or presence of a β-glucuronidase inhibitor D-saccharic acid-1,4-lactone (DSAL, 10 µM). Moreover, the voltage gated K⁺ current was determined in Jcam lymphoma cells by whole cell patch clamp following 24 hours incubation without or with recombinant human Klotho protein (50 ng/ml, 24 hours). K_v1.3 protein abundance in Jcam cells was determined utilising fluorescent antibodies in flow cytometry. Results: In K_v1.3 expressing Xenopus oocytes the K_v1.3 currents and the protein abundance of K_v1.3 were both significantly enhanced after treatment with recombinant human Klotho protein (50 ng/ml, 24 hours), an effect reversed by presence of DSAL. Moreover, treatment with recombinant human Klotho protein increased K_v currents and K_v1.3 protein abundance in Jcam cells. Conclusion: Alpha Klotho protein enhances K_v1.3 channel abundance and K_v1.3 currents in the plasma membrane, an effect depending on its β-glucuronidase activity.

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“…Klotho deficiency may also decrease extracellular volume through downregulation of the Na-K-2Cl cotransporter in the loop of Henle, with consequent increases in antidiuretic hormone and aldosterone hormonal responses, 27 both linked to the premature aging phenotype mediated by dehydration observed in klotho-deficient mice. 28 , 29 Outside the kidney, klotho can also function as β-glucuronidase to enhance creatine transporter-protein activity and maintain neuronal function and survival, 30 and to increase several K + channel expression and activities: 1) KCNQ1/KCNE1, required for proper hearing and cardiac repolarization; 31 2) voltage-gated K + channel (Kv1.3), 32 expressed in many tissues to regulate a wide variety of cellular functions, including excitability, cell proliferation, apoptosis, immune response, insulin sensitivity, and platelet function; 3) the cardiac K + channel, 33 a key channel for cardiac repolarization and deranged excitation following cardiac hypertrophy. 34 Furthermore, soluble klotho can also modulate the IGF-1 2 and Wnt 18 , 35 signaling pathways, playing a key role in antiaging, anti-tumor growth, and antifibrosis.…”

Section: Introductionmentioning

confidence: 99%

Klotho, stem cells, and aging

Bian¹,

Neyra

Zhan

et al. 2015

CIA

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Aging is an inevitable and progressive biological process involving dysfunction and eventually destruction of every tissue and organ. This process is driven by a tightly regulated and complex interplay between genetic and acquired factors. Klotho is an antiaging gene encoding a single-pass transmembrane protein, klotho, which serves as an aging suppressor through a wide variety of mechanisms, such as antioxidation, antisenescence, antiautophagy, and modulation of many signaling pathways, including insulin-like growth factor and Wnt. Klotho deficiency activates Wnt expression and activity contributing to senescence and depletion of stem cells, which consequently triggers tissue atrophy and fibrosis. In contrast, the klotho protein was shown to suppress Wnt-signaling transduction, and inhibit cell senescence and preserve stem cells. A better understanding of the potential effects of klotho on stem cells could offer novel insights into the cellular and molecular mechanisms of klotho deficiency-related aging and disease. The klotho protein may be a promising therapeutic agent for aging and aging-related disorders.

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Upregulation of KCNQ1/KCNE1 K⁺channels by Klotho

Cited by 13 publications

References 69 publications

β-Klotho as a Negative Regulator of the Peptide Transporters PEPT1 and PEPT2

β-Klotho as a Negative Regulator of the Peptide Transporters PEPT1 and PEPT2

Regulation of the Voltage Gated K<sup>+</sup> Channel K<sub>v1.3</sub> by Recombinant Human Klotho Protein

Klotho, stem cells, and aging

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