The LQLP Calcineurin Docking Site Is a Major Determinant of the Calcium-dependent Activation of Human TRESK Background K+ Channel

Czirják, Gábor; Enyedi, Péter

doi:10.1074/jbc.m114.577684

Cited by 20 publications

(28 citation statements)

References 44 publications

(73 reference statements)

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“…Indeed, the confirmed LxVP motif of KCNK18 (NTLqLP) contains a Leu in the Val position of this SLiM (Fig. 1E)25. The Pro pocket is also very shallow, allowing for a broad range of substitutions at this site.…”

Section: Resultsmentioning

confidence: 98%

Investigating the human Calcineurin Interaction Network using the πɸLxVP SLiM

Sheftic

Page

Peti

2016

Sci Rep

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Ser/thr phosphorylation is the primary reversible covalent modification of proteins in eukaryotes. As a consequence, it is the reciprocal actions of kinases and phosphatases that act as key molecular switches to fine tune cellular events. It has been well documented that ~400 human ser/thr kinases engage substrates via consensus phosphosite sequences. Strikingly, we know comparatively little about the mechanism by which ~40 human protein ser/thr phosphatases (PSPs) dephosphorylate ~15000 different substrates with high specificity. The identification of substrates of the essential PSP calcineurin (CN) has been exceptionally challenging and only a small fraction has been biochemically confirmed. It is now emerging that CN binds regulators and substrates via two short linear motifs (SLiMs), the well-studied PxIxIT SLiM and the LxVP SLiM, which remains controversial at the molecular level. Here we describe the crystal structure of CN in complex with its substrate NFATc1 and show that the LxVP SLiM is correctly defined as πɸLxVP. Bioinformatics studies using the πɸLxVP SLiM resulted in the identification of 567 potential CN substrates; a small subset was experimentally confirmed. This combined structural-bioinformatics approach provides a powerful method for dissecting the CN interaction network and for elucidating the role of CN in human health and disease.

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Section: Resultsmentioning

confidence: 98%

Investigating the human Calcineurin Interaction Network using the πɸLxVP SLiM

Sheftic

Page

Peti

2016

Sci Rep

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“…S8, C and D). In addition, we found that inhibition of TRESK dephosphorylation using the interfering peptide targeting serine 252, serine 262, serine 264, and serine 267 sites of TRESK, the identified dephosphorylation sites by calcineurin (17), could suppress the effects of calcineurin (10 enzyme units/l × 10 l) upon TRESK channels ( fig. S9).…”

Section: Decreased Calcineurin Abundance Mediates the Reduction Of Fumentioning

confidence: 92%

Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis

Yang

Jin

et al. 2018

Sci. Signal.

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Cancer-associated pain is debilitating. Understanding the mechanisms that cause it can inform drug development that may improve quality of life in patients. Here, we found that the reduced abundance of potassium channels called TRESK in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and cancer-associated pain. Overexpressing TRESK in DRG neurons suppressed tumor-induced neuronal hyperexcitability and pain hypersensitivity in bone metastasis model rats, whereas knocking down TRESK increased neuronal hyperexcitability and pain hypersensitivity in normal rats. Mechanistically, tumor-associated production of vascular endothelial growth factor (VEGF) activated the receptor VEGFR2 on DRGs, which increased the abundance of the calcineurin inhibitor DSCR1, which, in turn, decreased calcineurin-mediated activation of the transcription factor NFAT, thereby reducing the transcription of the gene encoding TRESK. Intrathecal application of exogenous calcineurin to tumor-bearing rats rescued TRESK abundance and abrogated both DRG hyperexcitability and pain hypersensitivity, whereas either inhibition or knockdown of calcineurin in normal rats reduced TRESK abundance and increased DRG excitability and pain sensitivity. These findings identify a potentially targetable mechanism that may cause bone metastasis–associated pain in cancer patients.

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“…It is well known that NFAT is the most important substrate of CaN. However, other molecules, such as Bad, Na + /H + exchanger, TWIK-related spinal cord potassium channel, and myocyte enhancer factor-2 transcription factor, are all downstream of CaN [55][56][57][58]. Unfortunately, these signaling molecules have scarcely been studied in PAH, and thus, little is known about their roles.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Pulmonary arterial hypertension (PAH) is a severe and debilitating disease characterized by remodeling of the pulmonary vessels, which is driven by excessive proliferation and migration and apoptosis resistance in pulmonary artery smooth muscle cells (PASMCs). The calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) signaling pathway is the most important downstream signaling pathway of store-operated Ca²⁺ entry (SOCE), which is increased in PAH. CaN/NFAT has been reported to contribute to abnormal proliferation in chronic hypoxia (CH)-induced PAH. However, the effect of CaN/NFAT signaling on PASMC proliferation, migration and apoptosis in monocrotaline (MCT)-induced PAH remains unclear. Methods: PAH rats were established by a single intraperitoneal injection of MCT for 21 days. PASMCs were isolated and cultured in normal and MCT-induced PAH Sprague-Dawley rat. PASMCs were treated with CsA targeting CaN and siRNA targeting NFATc2-4 gene respectively by liposome. We investigated the expression of calcineurin/NFAT signaling by immunofluorescence, qRT-PCR and Western blotting methods. Cell proliferation was monitored using MTS reagent or by assessing proliferating cell nuclear antigen (PCNA) expression. Cell apoptosis was evaluated with an Annexin V - FITC/propidium iodide (PI) apoptosis kit by flow cytometry. PASMC migration was assessed with a Transwell chamber. Results: MCT successfully induced PAH and pulmonary vascular remodeling in rats. CaN phosphatase activity and nuclear translocation of NFATc2-4 were increased in PASMCs derived from MCT-treated rats. In addition, CaNBβ/NFATc2-4 expression was amplified at the mRNA and protein levels. PASMC proliferation and migration were markedly inhibited in a dosedependent manner by cyclosporin A (CsA). Furthermore, siRNA targeting NFATc2 and NFATc4 attenuated the excessive proliferation and migration and apoptosis resistance in PASMCs derived from both CON and MCT-treated rats, while NFATc3 knockdown specifically affected MCT-PASMCs. Conclusion: Our results demonstrate that CaN/NFAT signaling is activated and involved in the modulation of PASMC proliferation, migration and apoptosis in MCT-induced PAH.

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The LQLP Calcineurin Docking Site Is a Major Determinant of the Calcium-dependent Activation of Human TRESK Background K+ Channel

Cited by 20 publications

References 44 publications

Investigating the human Calcineurin Interaction Network using the πɸLxVP SLiM

Investigating the human Calcineurin Interaction Network using the πɸLxVP SLiM

Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis

Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

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