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

Abstract:

: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.

journal_name

Sci Signal

journal_title

Science signaling

authors

Yang Y,Li S,Jin ZR,Jing HB,Zhao HY,Liu BH,Liang YJ,Liu LY,Cai J,Wan Y,Xing GG

doi

10.1126/scisignal.aao5150

subject

Has Abstract

pub_date

2018-10-16 00:00:00

issue

552

eissn

1945-0877

issn

1937-9145

pii

11/552/eaao5150

journal_volume

11

pub_type

杂志文章
  • 4E-BP2 hardwires lymphocytes for rapamycin sensitivity.

    abstract::The mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] inhibitor rapamycin is a potent inhibitor of T and B lymphocyte growth and proliferation. In this issue of Science Signaling, So et al found that the isoform of 4E-BP (4E-BP2) in lymphocytes that regulates messenger RNA translation is more sensitive...

    journal_title:Science signaling

    pub_type: 评论,杂志文章,评审

    doi:10.1126/scisignal.aaf8190

    authors: Abraham RT

    更新日期:2016-05-31 00:00:00

  • How Ca2+-permeable AMPA receptors, the kinase PKA, and the phosphatase PP2B are intertwined in synaptic LTP and LTD.

    abstract::Both synaptic long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical for memory formation. Dell'Acqua and co-workers now demonstrate that transient postsynaptic incorporation of Ca(2+)-permeable (CP) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is required for...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.aaf7067

    authors: Hell JW

    更新日期:2016-04-26 00:00:00

  • Inositol pyrophosphates as mammalian cell signals.

    abstract::Inositol pyrophosphates are highly energetic inositol polyphosphate molecules present in organisms from slime molds and yeast to mammals. Distinct classes of enzymes generate different forms of inositol pyrophosphates. The biosynthesis of these substances principally involves phosphorylation of inositol hexakisphospha...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.2001958

    authors: Chakraborty A,Kim S,Snyder SH

    更新日期:2011-08-23 00:00:00

  • Quantitative kinase and phosphatase profiling reveal that CDK1 phosphorylates PP2Ac to promote mitotic entry.

    abstract::The reciprocal regulation of phosphoprotein phosphatases (PPPs) by protein kinases is essential to cell cycle progression and control, particularly during mitosis for which the role of kinases has been extensively studied. PPPs perform much of the serine/threonine dephosphorylation in eukaryotic cells and achieve subs...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aba7823

    authors: Nasa I,Cressey LE,Kruse T,Hertz EPT,Gui J,Graves LM,Nilsson J,Kettenbach AN

    更新日期:2020-09-08 00:00:00

  • Transglutaminase-catalyzed protein-protein cross-linking suppresses the activity of the NF-κB-like transcription factor relish.

    abstract::Cross-linking of proteins by mammalian transglutaminases (TGs) plays important roles in physiological phenomena such as blood coagulation and skin formation. We show that Drosophila TG suppressed innate immune signaling in the gut. RNA interference (RNAi) directed against TG reduced the life span of flies reared under...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2003970

    authors: Shibata T,Sekihara S,Fujikawa T,Miyaji R,Maki K,Ishihara T,Koshiba T,Kawabata S

    更新日期:2013-07-23 00:00:00

  • mTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-β1-induced collagen biosynthesis.

    abstract::The differentiation of fibroblasts into a transient population of highly activated, extracellular matrix (ECM)-producing myofibroblasts at sites of tissue injury is critical for normal tissue repair. Excessive myofibroblast accumulation and persistence, often as a result of a failure to undergo apoptosis when tissue r...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aav3048

    authors: Selvarajah B,Azuelos I,Platé M,Guillotin D,Forty EJ,Contento G,Woodcock HV,Redding M,Taylor A,Brunori G,Durrenberger PF,Ronzoni R,Blanchard AD,Mercer PF,Anastasiou D,Chambers RC

    更新日期:2019-05-21 00:00:00

  • MicroRNAs add an additional layer to the complexity of cell signaling.

    abstract::MicroRNAs (miRNAs), key posttranscriptional regulators of many biological processes, have been implicated in many diseases, including cancer. In a recent paper, Avraham and colleagues take a systems biology approach to determine whether and how miRNAs are involved in the regulation of oncogenic signaling networks down...

    journal_title:Science signaling

    pub_type: 评论,杂志文章,评审

    doi:10.1126/scisignal.2002182

    authors: Herschkowitz JI,Fu X

    更新日期:2011-07-26 00:00:00

  • New connections: Manipulating NK cell responses.

    abstract::Manipulating ligand interactions with the activating receptor NKG2D modulates natural killer cell responses. ...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aan8369

    authors: Foley JF

    更新日期:2017-05-30 00:00:00

  • LRP6 mediates cAMP generation by G protein-coupled receptors through regulating the membrane targeting of Gα(s).

    abstract::Ligand binding to certain heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) stimulates the rapid synthesis of cyclic adenosine monophosphate (cAMP) through the G protein α(s) subunit, which activates adenylyl cyclase (AC). We found that the transmembrane receptor low-density lipop...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2001464

    authors: Wan M,Li J,Herbst K,Zhang J,Yu B,Wu X,Qiu T,Lei W,Lindvall C,Williams BO,Ma H,Zhang F,Cao X

    更新日期:2011-03-15 00:00:00

  • VGF, a new player in antidepressant action?

    abstract::Recent studies have identified adaptations of intracellular signaling pathways and target genes that could contribute or modulate the action of antidepressant drugs, as well as exercise-mediated antidepressant responses. Understanding these adaptations, particularly those changes that are common to diverse antidepress...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/stke.118pe19

    authors: Malberg JE,Monteggia LM

    更新日期:2008-05-06 00:00:00

  • Temperature-activated ion channels in neural crest cells confer maternal fever-associated birth defects.

    abstract::Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aal4055

    authors: Hutson MR,Keyte AL,Hernández-Morales M,Gibbs E,Kupchinsky ZA,Argyridis I,Erwin KN,Pegram K,Kneifel M,Rosenberg PB,Matak P,Xie L,Grandl J,Davis EE,Katsanis N,Liu C,Benner EJ

    更新日期:2017-10-10 00:00:00

  • Focus issue: fine-tuning Hedgehog signaling in development and disease.

    abstract::Hedgehog (Hh) signaling plays varied and critical roles in animal development, homeostasis, and disease. The core components of the canonical pathway and many key modulators of signaling have been identified, as have mechanisms by which the quantity and quality of signaling through the pathway are modulated. New resea...

    journal_title:Science signaling

    pub_type: 社论

    doi:10.1126/scisignal.2002653

    authors: VanHook AM

    更新日期:2011-11-22 00:00:00

  • Attenuation of rabies virulence: takeover by the cytoplasmic domain of its envelope protein.

    abstract::The capacity of a rabies virus to promote neuronal survival (a signature of virulence) or death (a marker of attenuation) depends on the cellular partners recruited by the PDZ-binding site (PDZ-BS) of its envelope glycoprotein (G). Neuronal survival requires the selective association of the PDZ-BS of G with the PDZ do...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2000510

    authors: Préhaud C,Wolff N,Terrien E,Lafage M,Mégret F,Babault N,Cordier F,Tan GS,Maitrepierre E,Ménager P,Chopy D,Hoos S,England P,Delepierre M,Schnell MJ,Buc H,Lafon M

    更新日期:2010-01-19 00:00:00

  • Beta-adrenergic regulation of the L-type Ca2+ channel Ca(V)1.2 by PKA rekindles excitement.

    abstract::When we are frightened, our hearts beat more rapidly and forcefully so we can fight more intensely or run away faster. This fight-or-flight response is triggered by the release of norepinephrine from neurons of the sympathetic nervous system. Norepinephrine activates the classic β-adrenergic receptor-heterotrimeric G(...

    journal_title:Science signaling

    pub_type: 评论,杂志文章

    doi:10.1126/scisignal.3141pe33

    authors: Hell JW

    更新日期:2010-09-28 00:00:00

  • Itk controls the spatiotemporal organization of T cell activation.

    abstract::During T cell activation by antigen-presenting cells (APCs), the diverse spatiotemporal organization of components of T cell signaling pathways modulates the efficiency of activation. Here, we found that loss of the tyrosine kinase interleukin-2 (IL-2)-inducible T cell kinase (Itk) in mice altered the spatiotemporal d...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2001821

    authors: Singleton KL,Gosh M,Dandekar RD,Au-Yeung BB,Ksionda O,Tybulewicz VL,Altman A,Fowell DJ,Wülfing C

    更新日期:2011-10-04 00:00:00

  • AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension.

    abstract::Endothelial cell dysfunction, characterized by a diminished response to endothelial cell-dependent vasodilators, is a hallmark of hypertension. TRPV4 channels play a major role in endothelial-dependent vasodilation, a function mediated by local Ca(2+) influx through clusters of functionally coupled TRPV4 channels rath...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2005052

    authors: Sonkusare SK,Dalsgaard T,Bonev AD,Hill-Eubanks DC,Kotlikoff MI,Scott JD,Santana LF,Nelson MT

    更新日期:2014-07-08 00:00:00

  • Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice.

    abstract::The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a nutrient-sensitive protein kinase that is aberrantly activated in many human cancers. Whether dysregulation of mTORC1 signaling in normal tissues increases the risk for cancer, however, is unknown. We focused on hepatocellular carcinoma, which has been l...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2002739

    authors: Menon S,Yecies JL,Zhang HH,Howell JJ,Nicholatos J,Harputlugil E,Bronson RT,Kwiatkowski DJ,Manning BD

    更新日期:2012-03-27 00:00:00

  • FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs.

    abstract::Frizzleds (FZDs) are a group of seven transmembrane-spanning (7TM) receptors that belong to class F of the G protein-coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aar5536

    authors: Wright SC,Cañizal MCA,Benkel T,Simon K,Le Gouill C,Matricon P,Namkung Y,Lukasheva V,König GM,Laporte SA,Carlsson J,Kostenis E,Bouvier M,Schulte G,Hoffmann C

    更新日期:2018-12-04 00:00:00

  • A direct screen for c-di-GMP modulators reveals a Salmonella Typhimurium periplasmic ʟ-arginine-sensing pathway.

    abstract::Cyclic-di-GMP (c-di-GMP) is a bacterial second messenger that transduces internal and external signals and regulates bacterial motility and biofilm formation. Some organisms encode more than 100 c-di-GMP-modulating enzymes, but only for a few has a signal been defined that modulates their activity. We developed and ap...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aaa1796

    authors: Mills E,Petersen E,Kulasekara BR,Miller SI

    更新日期:2015-06-09 00:00:00

  • Costimulatory role of CXCR4 with pre-TCR and its crosstalk with PI3K in beta-selection of thymocytes.

    abstract::Chemokines were initially thought of only as regulators of the migration of developing thymocytes between different compartments of the thymus and were predicted also to be involved in early stages of thymocyte development. Recent data have suggested additional functions for the chemokine receptor CXCR4-a G protein-co...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.3119jc4

    authors: Ahamed JA,Madhivadhani P

    更新日期:2010-04-27 00:00:00

  • Tuning the regulator: Phosphorylation of KCC2 at two specific sites is critical for neurodevelopment.

    abstract::The K+/Cl- cotransporter KCC2 is a molecular switch between excitatory and inhibitory effects of GABAergic inputs into neurons. In a pair of exciting studies, Watanabe et al. and Pisella et al. elucidate the role of KCC2 dephosphorylation in this process and reveal its consequences for neurodevelopment and nervous sys...

    journal_title:Science signaling

    pub_type: 评论,杂志文章,评审

    doi:10.1126/scisignal.aay8960

    authors: Zamponi GW

    更新日期:2019-10-15 00:00:00

  • The role of ciliary trafficking in Hedgehog receptor signaling.

    abstract::Defects in the biogenesis of or transport through primary cilia affect Hedgehog protein signaling, and many Hedgehog pathway components traffic through or accumulate in cilia. The Hedgehog receptor Patched negatively regulates the activity and ciliary accumulation of Smoothened, a seven-transmembrane protein that is e...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aaa5622

    authors: Kim J,Hsia EY,Brigui A,Plessis A,Beachy PA,Zheng X

    更新日期:2015-06-02 00:00:00

  • Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis.

    abstract::Like phosphorylation, the addition of O-linked beta-N-acetylglucosamine (O-GlcNAcylation) is a ubiquitous, reversible process that modifies serine and threonine residues on nuclear and cytoplasmic proteins. Overexpression of the enzyme that adds O-GlcNAc to target proteins, O-GlcNAc transferase (OGT), perturbs cytokin...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2000526

    authors: Wang Z,Udeshi ND,Slawson C,Compton PD,Sakabe K,Cheung WD,Shabanowitz J,Hunt DF,Hart GW

    更新日期:2010-01-12 00:00:00

  • Acute O2 sensing through HIF2α-dependent expression of atypical cytochrome oxidase subunits in arterial chemoreceptors.

    abstract::Acute cardiorespiratory responses to O2 deficiency are essential for physiological homeostasis. The prototypical acute O2-sensing organ is the carotid body, which contains glomus cells expressing K+ channels whose inhibition by hypoxia leads to transmitter release and activation of nerve fibers terminating in the brai...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aay9452

    authors: Moreno-Domínguez A,Ortega-Sáenz P,Gao L,Colinas O,García-Flores P,Bonilla-Henao V,Aragonés J,Hüttemann M,Grossman LI,Weissmann N,Sommer N,López-Barneo J

    更新日期:2020-01-21 00:00:00

  • Controlling the number of tooth rows.

    abstract::The organization and renewal capacity of teeth vary greatly among vertebrates. Mammals have only one row of teeth that are renewed at most once, whereas many nonmammalian species have multirowed dentitions and show remarkable capacity to replace their teeth throughout life. Although knowledge on the genetic basis of t...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.285pe53

    authors: Mikkola ML

    更新日期:2009-08-25 00:00:00

  • Human regulatory T cells rapidly suppress T cell receptor-induced Ca(2+), NF-κB, and NFAT signaling in conventional T cells.

    abstract::CD4(+)CD25(hi)Foxp3(+) regulatory T cells (T(regs)) are critical mediators of self-tolerance, which is crucial for the prevention of autoimmune disease, but T(regs) can also inhibit antitumor immunity. T(regs) inhibit the proliferation of CD4(+)CD25(-) conventional T cells (T(cons)), as well as the ability of these ce...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2002179

    authors: Schmidt A,Oberle N,Weiss EM,Vobis D,Frischbutter S,Baumgrass R,Falk CS,Haag M,Brügger B,Lin H,Mayr GW,Reichardt P,Gunzer M,Suri-Payer E,Krammer PH

    更新日期:2011-12-20 00:00:00

  • Large-scale discovery of ERK2 substrates identifies ERK-mediated transcriptional regulation by ETV3.

    abstract::The mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 2 (ERK2) is ubiquitously expressed in mammalian tissues and is involved in a wide range of biological processes. Although MAPKs have been intensely studied, identification of their substrates remains challenging. We have optimized a chem...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2002010

    authors: Carlson SM,Chouinard CR,Labadorf A,Lam CJ,Schmelzle K,Fraenkel E,White FM

    更新日期:2011-10-25 00:00:00

  • Increased MKK4 abundance with replicative senescence is linked to the joint reduction of multiple microRNAs.

    abstract::MKK4 (mitogen-activated protein kinase kinase 4) is a pivotal upstream activator of c-Jun N-terminal kinase and p38. Here, we report that the abundance of MKK4 increases in senescent human diploid fibroblasts through enhanced translation. We identified four microRNAs (miR-15b, miR-24, miR-25, and miR-141) that target ...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2000442

    authors: Marasa BS,Srikantan S,Masuda K,Abdelmohsen K,Kuwano Y,Yang X,Martindale JL,Rinker-Schaeffer CW,Gorospe M

    更新日期:2009-10-27 00:00:00

  • Noncanonical NF-κB signaling is limited by classical NF-κB activity.

    abstract::Precise regulation of nuclear factor κB (NF-κB) signaling is crucial for normal immune responses, and defective NF-κB activity underlies a range of immunodeficiencies. NF-κB is activated through two signaling cascades: the classical and noncanonical pathways. The classical pathway requires inhibitor of κB kinase β (IK...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2004557

    authors: Gray CM,Remouchamps C,McCorkell KA,Solt LA,Dejardin E,Orange JS,May MJ

    更新日期:2014-02-04 00:00:00

  • Bacterial invaders drive CRC progression.

    abstract::The oral bacterium Fusobacterium nucleatum is often found in colorectal cancer (CRC). In the 21 July 2020 issue of Science Signaling, Casasanta et al show that CRC cell-resident F. nucleatum promotes cytokine secretion that may potentiate tumor growth and metastatic progression in patients. ...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.abc4218

    authors: Meyerson M

    更新日期:2020-08-11 00:00:00