The Epithelial Calcium Channel TRPV5 Is Regulated Differentially by Klotho and Sialidase

Leunissen, E. H. P.; Nair, Anil V.; Büll, Christian; Lefeber, Dirk; Delft, Floris L. van; Bindels, René J. M.; Hoenderop, Joost G. J.

doi:10.1074/jbc.m113.473520

Cited by 44 publications

(32 citation statements)

References 38 publications

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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

5,279

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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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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

5,279

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“…The reversal of the effect of Klotho indicates that the effect of Klotho on Slc6A8 indeed requires β-glucuronidase activity of Klotho. Previous studies suggested that Klotho may regulate ion channels by removing terminal sialic acids [5,6]. …”

Section: Discussionmentioning

confidence: 99%

“…The extracellular domain of the Klotho protein may function as enzyme with β-glucuronidase activity and, after being cleaved off, as hormone [3,4,5,6,7]. Klotho expression is a decisive determinant of ageing and life span [8,9].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of the Creatine Transporter Slc6A8 by Klotho

Almilaji

Sopjani

Elvira

et al. 2014

Kidney Blood Press Res

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Background/Aims: The transmembrane Klotho protein contributes to inhibition of 1,25(OH)₂D₃ formation. The extracellular domain of Klotho protein could function as an enzyme with e.g. β-glucuronidase activity, be cleaved off and be released into blood and cerebrospinal fluid. Klotho regulates several cellular transporters. Klotho protein deficiency accelerates the appearance of age related disorders including neurodegeneration and muscle wasting and eventually leads to premature death. The main site of Klotho protein expression is the kidney. Klotho protein is also appreciably expressed in other tissues including chorioid plexus. The present study explored the effect of Klotho protein on the creatine transporter CreaT (Slc6A8), which participates in the maintenance of neuronal function and survival. Methods: To this end cRNA encoding Slc6A8 was injected into Xenopus oocytes with and without additional injection of cRNA encoding Klotho protein. Creatine transporter CreaT (Slc6A8) activity was estimated from creatine induced current determined by two-electrode voltage-clamp. Results: Coexpression of Klotho protein significantly increased creatine-induced current in Slc6A8 expressing Xenopus oocytes. Coexpression of Klotho protein delayed the decline of creatine induced current following inhibition of carrier insertion into the cell membrane by brefeldin A (5 µM). The increase of creatine induced current by coexpression of Klotho protein in Slc6A8 expressing Xenopus oocytes was reversed by β-glucuronidase inhibitor (DSAL). Similarly, treatment of Slc6A8 expressing Xenopus oocytes with recombinant human alpha Klotho protein significantly increased creatine induced current. Conclusion: Klotho protein up-regulates the activity of creatine transporter CreaT (Slc6A8) by stabilizing the carrier protein in the cell membrane, an effect requiring β-glucuronidase activity of Klotho protein.

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“…The extracellular domain of the Klotho protein may be cleaved off and function as enzyme with β-glucuronidase activity [3,4,5,6,7]. Klotho has a powerful impact on aging and life span [8,9].…”

Section: Introductionmentioning

confidence: 99%

Up-Regulation of Excitatory Amino Acid Transporters EAAT1 and EAAT2 by ß-Klotho

Warsi

Abousaab²,

Läng

2015

Neurosignals

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Background/Aims: Klotho, a transmembrane protein expressed in chorioid plexus of the brain, kidney, and several other tissues, is required 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. At least in part by exerting β-glucuronidase activity, soluble klotho regulates several ion channels and carriers. Klotho protein deficiency accelerates the appearance of age related disorders including neurodegeneration and muscle wasting and eventually leads to premature death. The present study explored the effect of Klotho protein on the excitatory glutamate transporters EAAT1 (SLC1A3) and EAAT2 (SLC1A2), Na⁺ coupled carriers clearing excitatory amino acids from the synaptic cleft and thus participating in the regulation of neuronal excitability. Methods: cRNA encoding EAAT1 or EAAT2 was injected into Xenopus laevis oocytes and glutamate (2 mM)-induced inward current (I_Glu) taken as measure of glutamate transport. Measurements were made without or with prior 24 h treatment with soluble ß-Klotho protein (30 ng/ml) in the absence and presence of β-glucuronidase inhibitor D-saccharic acid 1,4-lactone monohydrate (DSAL,10 µM). Results: I_Glu was observed in EAAT1 and in EAAT2 expressing oocytes but not in water injected oocytes. In both, EAAT1 and EAAT2 expressing oocytes I_Glu was significantly increased by treatment with soluble ß-Klotho protein, an effect reversed by DSAL. Treatment with ß-klotho protein increased significantly the maximal transport rate without significantly modifying the affinity of the carriers. Conclusion: ß-Klotho up-regulates the excitatory glutamate transporters EAAT1 and EAAT2 and thus participates in the regulation of neuronal excitation.

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The Epithelial Calcium Channel TRPV5 Is Regulated Differentially by Klotho and Sialidase

Cited by 44 publications

References 38 publications

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

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

Upregulation of the Creatine Transporter Slc6A8 by Klotho

Up-Regulation of Excitatory Amino Acid Transporters EAAT1 and EAAT2 by ß-Klotho

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