Upregulation of the Creatine Transporter Slc6A8 by Klotho

Almilaji, Ahmad; Sopjani, Mentor; Elvira, Bernat; Borrás, José; Dërmaku-Sopjani, Miribane; Muñoz, Carlos; Warsi, Jamshed; Lang, Undine E.; Läng, Florian

doi:10.1159/000368462

Cited by 43 publications

(38 citation statements)

References 85 publications

(105 reference statements)

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“…In theory, JAK3 could, through this pathway, up-regulate the expression of CreaT regulating signalling molecules. Regulators of CreaT include JAK2 [65], AMPK [66,67], PKC [68], SPAK [61], OSR1 [61], PIKfyve [69], mTOR [70], SGK1 [71], SGK3 [71], klotho [56], and peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α) or beta (PGC-1β) [72]. …”

Section: Discussionmentioning

confidence: 99%

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Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by the Janus Kinase JAK3

2015

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Background: The creatine transporter CreaT (SLC6A8), a Na⁺,Cl^- coupled transporter is expressed in diverse tissues including the brain. Genetic defects of SLC6A8 result in mental retardation with seizures. The present study explored the regulation of CreaT by Janus kinase JAK3, which is expressed in a variety of tissues including the brain and participates in the regulation of cell survival and differentiation of neuronal precursor cells. Methods: CreaT was expressed in Xenopus laevis oocytes with or without wild-type JAK3, constitutively active ^A568VJAK3 and inactive ^K851AJAK3. Creatine transport in those oocytes was quantified utilizing dual electrode voltage clamp. Results: Electrogenic creatine transport was observed in CreaT expressing oocytes but not in water-injected oocytes. In CreaT expressing oocytes co-expression of JAK3 or ^A568VJAK3, but not co-expression of ^K851AJAK3 was followed by a significant decrease of creatine induced current. According to kinetic analysis JAK3 significantly decreased the maximal creatine transport rate. In CreaT and JAK3 expressing oocytes the creatine induced current was significantly increased by JAK3 inhibitor WHI-P154 (22 µM). Conclusion: JAK3 is a powerful negative regulator of the creatine transporter CreaT.

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Section: Discussionmentioning

confidence: 99%

“…The cDNA constructs encoding wild-type SLC6A8 (CreaT) [2], wild-type murine JAK3 (Imagenes, Berlin, Germany), gain of function mutant A568V JAK3 [17] and inactive mutant K851A JAK3 [17] were used for generation of cRNA as described previously [55,56]. …”

Section: Methodsmentioning

confidence: 99%

Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by the Janus Kinase JAK3

2015

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“…Constructs encoding human wild-type EAAT1 [65] and human wild-type EAAT2 [66,67,68], were used for generation of cRNA as described previously [69,70]. …”

Section: Methodsmentioning

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 flow rate of the superfusion was approx. 20 ml/min, and a complete exchange of the bath solution was reached within about 10 s [63][64][65].…”

Section: Voltage Clamp In Xenopus Oocytesmentioning

confidence: 99%

Up-Regulation of the Excitatory Amino Acid Transporters EAAT1 and EAAT2 by Mammalian Target of Rapamycin

Abousaab¹,

Uzcátegui²,

Elsir³

et al. 2016

Cell Physiol Biochem

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Background:The excitatory amino-acid transporters EAAT1 and EAAT2 clear glutamate from the synaptic cleft and thus terminate neuronal excitation. The carriers are subject to regulation by various kinases. The EAAT3 isoform is regulated by mammalian target of rapamycin (mTOR). The present study thus explored whether mTOR influences transport by EAAT1 and/or EAAT2. Methods: cRNA encoding wild type EAAT1 (SLC1A3) or EAAT2 (SLC1A2) was injected into Xenopus oocytes without or with additional injection of cRNA encoding mTOR. Dual electrode voltage clamp was performed in order to determine electrogenic glutamate transport (I EAAT ). EAAT2 protein abundance was determined utilizing chemiluminescence. Results: Appreciable I EAAT was observed in EAAT1 or EAAT2 expressing but not in water injected oocytes. I EAAT was significantly increased by coexpression of mTOR. Coexpression of mTOR increased significantly the maximal I EAAT in EAAT1 or EAAT2 expressing oocytes, without significantly modifying affinity of the carriers. Moreover, coexpression of mTOR increased significantly EAAT2 protein abundance in the cell membrane. Conclusions: The kinase mTOR up-regulates the excitatory amino acid transporters EAAT1 and EAAT2.

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Upregulation of the Creatine Transporter Slc6A8 by Klotho

Cited by 43 publications

References 85 publications

Regulation of the Na<sup>+</sup>,Cl<sup>-</sup> Coupled Creatine Transporter CreaT (SLC6A8) by the Janus Kinase JAK3

Regulation of the Na<sup>+</sup>,Cl<sup>-</sup> Coupled Creatine Transporter CreaT (SLC6A8) by the Janus Kinase JAK3

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

Up-Regulation of the Excitatory Amino Acid Transporters EAAT1 and EAAT2 by Mammalian Target of Rapamycin

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