The Role of Janus Kinase 3 in the Regulation of Na+/K+ ATPase under Energy Depletion

Hosseinzadeh, Zohreh; Honisch, Sabina; Schmid, Evi; Jilani, Kashif; Szteyn, Kalina; Bhavsar, Shefalee K.; Singh, Yogesh; Palmada, Mònica; Umbach, Anja T.; Shumilina, Ekaterina; Läng, Florian

doi:10.1159/000430133

Cited by 24 publications

(26 citation statements)

References 56 publications

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Section: Discussionmentioning

confidence: 99%

“…The observation may be, however, related to the JAK3 sensitivity of Na + /K + -ATPase [49]. JAK3 is a powerful inhibitor of Na + /K + ATPase activity thus contributing to the maintenance of cytosolic ATP concentration during energy depletion [49]. ATP consumption by the Na + /K + ATPase is substantial and inhibition of Na + /K + -ATPase activity thus significantly contributes to energy conservation and cell survival during a transient period of energy shortage [49].…”

Section: Discussionmentioning

confidence: 99%

“…The pleotropic effects of JAK3 include regulation of transport across the cell membrane [43,45,49,50,51,52,53,54] including the excitatory amino acid transporters [53] and the Na + /K + ATPase [49]. …”

Section: Introductionmentioning

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%

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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“…Intracellular ATP measurement by luciferase-based assay (ATP Bioluminescence Assay kit CLS II, Roche Diagnostics and Sigma) was performed as described earlier (73). Data were normalized with Th0 cells, performed in triplicate, and relative ATP levels estimated.…”

Section: Methodsmentioning

confidence: 99%

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Singh

Zhou

Shi

et al. 2016

Journal of Biological Chemistry

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CD4؉ T helper 9 (Th9) cells are a newly discovered Th cell subset that produce the pleiotropic cytokine IL-9. Th9 cells can protect against tumors and provide resistance against helminth infections. Given their pivotal role in the adaptive immune system, understanding Th9 cell development and the regulation of IL-9 production could open novel immunotherapeutic opportunities. The Na ؉ /H ؉ exchanger 1 (NHE1; gene name Slc9␣1)) is critically important for regulating intracellular pH (pH i ), cell volume, migration, and cell survival. The pH i influences cytokine secretion, activities of membrane-associated enzymes, ion transport, and other effector signaling molecules such as ATP and Ca 2؉ levels. However, whether NHE1 regulates Th9 cell development or IL-9 secretion has not yet been defined. The present study explored the role of NHE1 in Th9 cell development and function. Th cell subsets were characterized by flow cytometry and pH i was measured using 2,7-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein-acetoxymethyl ester (BCECF-AM) dye. NHE1 functional activity was estimated from the rate of realkalinization following an ammonium pulse. Surprisingly, in Th9 cells pH i and NHE1 activity were significantly higher than in all other Th cell subsets (Th1/Th2/Th17 and induced regulatory T cells (iTregs)). NHE1 transcript levels and protein abundance were significantly higher in Th9 cells than in other Th cell subsets. Inhibition of NHE1 by siRNA-NHE1 or with cariporide in Th9 cells down-regulated IL-9 and ATP production. NHE1 activity, Th9 cell development, and IL-9 production were further blunted by pharmacological inhibition of protein kinase Akt1/Akt2. Our findings reveal that Akt1/Akt2 control of NHE1 could be an important physiological regulator of Th9 cell differentiation, IL-9 secretion, and ATP production. CD4ϩ T cells participate in the regulation of the immune response during infections, autoimmunity, and cancer. CD4 ϩ T cells are an important and essential arm of the adaptive immune system (1). CD4 ϩ T cells can be divided into various subtypes based upon their cytokine secretion: T helper 1 (Th1) 4 cells produce IFN-␥ (1, 2), Th2 cells produce IL-4, IL-5, and IL-13 (3), Th17 cells produce IL-17 (4 -6), Th9 cells produce IL-9 (7-9), and suppressive regulatory T cells (Tregs) produce TGF-␤ and IL-10 (10). A great deal of experimental effort has been dedicated to decipher the development and function of various Th cell subsets. However, Th9 cell development and function remain incompletely understood.Th9 cells are a recently characterized Th cell subset recognized by their potent production of IL-9. Th9 cells play a pivotal role in health and disease. Th9 cells have been shown to exacerbate the airway allergic immune response by recruiting eosinophils and mast cells to the lungs, increasing mucus production, and production of serum IgE (11, 12). Th9 cells further contribute to the host-immune reaction against helminth infections and tumors (7, 13-23). The development and function of Th9 cells are regulated ...

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“…For generation of cRNA [43,44], constructs were used encoding wild-type mTOR [45], EAAT1 [46] and EAAT2 [47][48][49]. The constructs were sequenced to verify the correctness of the plasmid [50].…”

Section: Constructsmentioning

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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The Role of Janus Kinase 3 in the Regulation of Na+/K+ ATPase under Energy Depletion

Cited by 24 publications

References 56 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

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

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

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