Janus kinase 3 regulates renal 25-hydroxyvitamin D 1α-hydroxylase expression, calcitriol formation, and phosphate metabolism

Umbach, Anja T.; Zhang, Bingbing; Daniel, Christoph; Fajol, Abul; Velić, Ana; Hosseinzadeh, Zohreh; Bhavsar, Shefalee K.; Bock, C.‐Thomas; Kandolf, Reinhard; Pichler, Bernd J.; Amann, Kerstin; Föller, Michael; Läng, Florian

doi:10.1038/ki.2014.371

Cited by 23 publications

(23 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the difference between B lymphocytes from jak3 -/-mice and jak3 +/+ mice may be affected by an influence of JAK3 deficiency on the abundance of inflammatory cells and the release of inflammatory mediators modifying BK channel activity. Along those lines enhanced serum calcitriol and FGF23 levels have been observed in jak3 -/-mice [57]: Moreover, JAK3-deficient mice are volume depleted [48].…”

Section: Discussionmentioning

confidence: 99%

Regulation of Large Conductance Voltage-and Ca2+-Activated K+ Channels by the Janus Kinase JAK3

Warsi

Singh

Elvira

et al. 2015

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

Background/Aims: Janus kinase 3 (JAK3), a tyrosine kinase contributing to the regulation of cell proliferation and apoptosis of lymphocytes and tumour cells, has been shown to modify the expression and function of several ion channels and transport proteins. Channels involved in the regulation of cell proliferation include the large conductance voltage- and Ca²⁺-activated K⁺ channel BK. The present study explored whether JAK3 modifies BK channel protein abundance and current. Methods: cRNA encoding Ca²⁺-insensitive BK channel (BK^{M513I+Δ899-903}) was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild-type JAK3, constitutively active ^A568VJAK3, or inactive ^K851AJAK3. Voltage gated K⁺ channel activity was measured utilizing dual electrode voltage clamp. Moreover, BK channel protein abundance was determined utilizing flow cytometry in CD19⁺ B lymphocyte cell membranes from mice lacking functional JAK3 (jak3^-/-) and corresponding wild-type mice (jak3^+/+). Results: BK activity in BK^{M513I+Δ899-903} expressing oocytes was slightly but significantly decreased by coexpression of wild-type JAK3 and of ^A568VJAK3, but not by coexpression of ^K851AJAK3. The BK channel protein abundance in the cell membrane was significantly higher in jak3^-/- than in jak3^+/+ B lymphocytes. The decline of conductance in BK and JAK3 coexpressing oocytes following inhibition of channel protein insertion by brefeldin A (5 µM) was similar in oocytes expressing BK with JAK3 and oocytes expressing BK alone, indicating that JAK3 might slow channel protein insertion into rather than accelerating channel protein retrieval from the cell membrane. Conclusion: JAK3 is a weak negative regulator of membrane BK protein abundance and activity.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of Large Conductance Voltage-and Ca2+-Activated K+ Channels by the Janus Kinase JAK3

Warsi

Singh

Elvira

et al. 2015

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

show abstract

“…In JAK3 deficient mice spleen, peripheral lymph nodes, and thymus are hypoplastic, and intestinal Peyer's patches completely lacking [18]. Jak3-deficiency leads to increased formation of 1,25(OH) 2 D 3 in the kidney [19] and to enhanced release of IL-12 [20], which is produced by several cell types including dendritic cells [21].…”

Section: Introductionmentioning

confidence: 99%

Impact of Janus Kinase 3 on Cellular Ca2+ Release, Store Operated Ca2+ Entry and Na+/Ca2+ Exchanger Activity in Dendritic Cells

Yan

Schmid

Hosseinzadeh

et al. 2015

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

Background/Aims: Janus kinase 3 (JAK3), a tyrosine kinase mainly expressed in hematopoietic cells, participates in the signaling stimulating cell proliferation. The kinase is expressed in dendritic cells (DCs), antigen presenting cells involved in the initiation and regulation of antigen-specific T-cell responses. Dendritic cell function is regulated by cytosolic Ca²⁺ activity ([Ca²⁺]_i). Mediators increasing [Ca²⁺]_i in DCs include ATP and the chemokine receptor CXCR4 ligand CXCL12. The present study explored, whether JAK3 participates in the regulation of [Ca²⁺]_i in DCs. Methods: Fura-2 fluorescence was employed to determine [Ca²⁺]_i, and whole cell patch clamp to decipher electrogenic transport in immature DCs isolated from bone marrow of JAK3-knockout (jak3^-/-) or wild-type mice (jak3^+/+). Results: Without treatment, [Ca²⁺]_i was similar in jak3^-/- and jak3^+/+ DCs. Addition of ATP (100 µM) was followed by transient increase of [Ca²⁺]_i reflecting Ca²⁺ release from intracellular stores, an effect significantly less pronounced in jak3^-/- DCs than in jak3^+/+ DCs. CXCL12 administration was followed by a sustained increase of [Ca²⁺]_i reflecting receptor operated Ca²⁺ entry, an effect significantly less rapid in jak3^-/- DCs than in jak3^+/+ DCs. In addition, the Ca²⁺ release-activated Ca²⁺ channel (CRAC) current triggered by IP₃-induced Ca²⁺ store depletion and CXCL12 was significantly higher in DCs from jak3^+/+ mice than in jak3^-/- mice. Inhibition of sarcoendoplasmatic reticulum Ca²⁺-ATPase (SERCA) by thapsigargin (1 µM) in the absence of extracellular Ca²⁺ was followed by a transient increase of [Ca²⁺]_i reflecting Ca²⁺ release from intracellular stores, and subsequent readdition of extracellular Ca²⁺ in the continued presence of thapsigargin was followed by a sustained increase of [Ca²⁺]_i reflecting store operated Ca²⁺ entry (SOCE). Both, Ca²⁺ release from intracellular stores and SOCE were again significantly lower in jak3^-/- DCs than in jak3^+/+ DCs. Pretreatment of jak3^+/+ DCs with JAK inhibitor WHI-P154 (22 µM, 10 minutes or 24 hours) significantly blunted both thapsigargin induced Ca²⁺ release and subsequent SOCE. Abrupt replacement of Na⁺ containing (130 mM) and Ca²⁺ free (0 mM) extracellular bath by Na⁺ free (0 mM) and Ca²⁺ containing (2 mM) extracellular bath increased [Ca²⁺]_i reflecting Na⁺/Ca²⁺ exchanger activity, an effect again significantly less pronounced in jak3^-/- DCs than in jak3^+/+DCs. Conclusions: JAK3 defi...

show abstract

“…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%

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

2015

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Janus kinase 3 regulates renal 25-hydroxyvitamin D 1α-hydroxylase expression, calcitriol formation, and phosphate metabolism

Cited by 23 publications

References 74 publications

Regulation of Large Conductance Voltage-and Ca2+-Activated K+ Channels by the Janus Kinase JAK3

Regulation of Large Conductance Voltage-and Ca2+-Activated K+ Channels by the Janus Kinase JAK3

Impact of Janus Kinase 3 on Cellular Ca2+ Release, Store Operated Ca2+ Entry and Na+/Ca2+ Exchanger Activity in Dendritic Cells

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

Contact Info

Product

Resources

About