Abstract:
:TRPM2 is a Ca2+-permeable cation channel that is specifically activated by adenosine diphosphoribose (ADPR). Channel activation in the plasma membrane leads to Ca2+ influx and has been linked to apoptotic mechanisms. The primary agonist, ADPR, is produced both extra- and intracellularly and causes increases in intracellular calcium concentration ([Ca2+]i), but the mechanisms involved are not understood. Using short interfering RNA and a knockout mouse, we report that TRPM2, in addition to its role as a plasma membrane channel, also functions as a Ca2+-release channel activated by intracellular ADPR in a lysosomal compartment. We show that both functions of TRPM2 are critically linked to hydrogen peroxide-induced beta cell death. Additionally, extracellular ADPR production by the ectoenzyme CD38 from its substrates NAD+ (nicotinamide adenine dinucleotide) or cADPR causes IP3-dependent Ca2+ release via P2Y and adenosine receptors. Thus, ADPR and TRPM2 represent multimodal signaling elements regulating Ca2+ mobilization in beta cells through membrane depolarization, Ca2+ influx, and release of Ca2+ from intracellular stores.
journal_name
Sci Signaljournal_title
Science signalingauthors
Lange I,Yamamoto S,Partida-Sanchez S,Mori Y,Fleig A,Penner Rdoi
10.1126/scisignal.2000278subject
Has Abstractpub_date
2009-05-19 00:00:00pages
ra23issue
71eissn
1945-0877issn
1937-9145pii
2/71/ra23journal_volume
2pub_type
杂志文章abstract::TRPML1 (transient receptor potential mucolipin 1) is a Ca2+-permeable, nonselective cation channel localized to the membranes of endosomes and lysosomes and is not present or functional on the plasma membrane. Ca2+ released from endosomes and lysosomes into the cytosol through TRPML1 channels is vital for trafficking,...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aba1015
更新日期:2020-06-23 00:00:00
abstract::Eps15 homology domain (EHD) proteins are conserved adenosine triphosphatases that are involved in membrane remodeling. EHD family members are structurally similar to the guanosine triphosphatase (GTPase) dynamin, and both are essential for the fission step of clathrin-mediated endocytosis. This Journal Club highlights...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.2002989
更新日期:2012-04-24 00:00:00
abstract::The hypoxia inducible factors (HIFs) and CCAAT/enhancer binding protein alpha (C/EBP alpha) are transcription factors that mediate adaptive responses to hypoxia and control aspects of energy metabolism, respectively. New evidence suggests that when HIF-1 alpha and C/EBP alpha interact, they bring about reciprocal func...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.143jc2
更新日期:2008-10-28 00:00:00
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
更新日期:2011-10-25 00:00:00
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
更新日期:2020-01-21 00:00:00
abstract::Pentraxin 3 (PTX3), a member of the long pentraxin subfamily within the family of pentraxins, is a soluble pattern recognition molecule that functions in the innate immune system. Innate immunity affords the infected host protection against sepsis, a potentially life-threatening inflammatory response to infection. Ext...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2005522
更新日期:2014-09-16 00:00:00
abstract::The fluorescent properties of the amino acid tryptophan make it a useful tool for fluorometric assays. Because tryptophan fluorescence is remarkably sensitive to the polarity of the environment, it can be used to determine the affinity of tryptophan-containing peptides for phospholipid vesicles of varying compositions...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.299pl4
更新日期:2009-12-01 00:00:00
abstract::The symbiotic interaction between Rhizobium bacteria and legume plants leads to the induction of a new developmental program: the formation of nitrogen-fixing root nodules. Nodulation is triggered by specific bacterial signals, the Nod factors, and integrates plant developmental regulatory pathways to reactivate diffe...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.149re11
更新日期:2008-12-09 00:00:00
abstract::Activation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by VEGF binding is critical for vascular morphogenesis. In addition, VEGF disrupts the endothelial barrier by triggering the phosphorylation and turnover of the junctional molecule VE-cadherin, a process mediated by the VEGFR2 downstream effec...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aad9256
更新日期:2016-07-19 00:00:00
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
更新日期:2015-06-09 00:00:00
abstract::Slit proteins act as repulsive axon guidance cues by activating receptors of the Roundabout (Robo) family. During early neurogenesis in Drosophila melanogaster, Slit prevents the growth cones of longitudinal tract neurons from inappropriately crossing the midline, thus restricting these cells to trajectories parallel ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aam5841
更新日期:2017-06-20 00:00:00
abstract::In a mouse model of Parkinson's disease, new evidence shows that l-DOPA, which is used to treat the symptoms of the disease but also causes dyskinesia, results in a persistent activation of the protein kinase mTOR (mammalian target of rapamycin) in a subset of striatal medium spiny neurons. Moreover, blockade of a spe...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.280pe42
更新日期:2009-07-21 00:00:00
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
更新日期:2017-10-10 00:00:00
abstract::Genetic diversity in human natural killer (NK) cell receptors is linked to resistance and susceptibility to many diseases. Here, we tested the effect of this diversity on the nanoscale organization of killer cell immunoglobulin-like receptors (KIRs). Using superresolution microscopy, we found that inhibitory KIRs enco...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aaw9252
更新日期:2019-12-17 00:00:00
abstract::MicroRNAs (miRNAs) are small noncoding RNAs that suppress the abundance of partially complementary mRNAs and inhibit their translation. Each miRNA can regulate hundreds of mRNAs, sometimes strongly but often weakly, to mediate a diverse array of biological functions, including proliferation, cell signaling, differenti...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.2005825
更新日期:2015-03-17 00:00:00
abstract::Chemoattractants induce cell migration through the activation of a distinct family of structurally related heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors. Over the past few years, several receptors in this family have been identified that recognize different classes of chemoattractants...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.259pe10
更新日期:2009-02-24 00:00:00
abstract::The mechanisms that determine localized formation of reactive oxygen species (ROS) through NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase (Nox) family members in nonphagocytic cells are unknown. We show that the c-Src substrate proteins Tks4 (tyrosine kinase substrate with four SH3 domains...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2000370
更新日期:2009-09-15 00:00:00
abstract::Individual signaling pathways operate in the context of the broader signaling network. Thus, the response of a cell to signals from the environment is affected by the state of the signaling network, such as the clinically relevant example of whether some components in the network are inhibited. The cytokine tumor necr...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aac7235
更新日期:2015-12-15 00:00:00
abstract::Oxytocin and vasopressin mediate various physiological functions that are important for osmoregulation, reproduction, cardiovascular function, social behavior, memory, and learning through four G protein-coupled receptors that are also implicated in high-profile disorders. Targeting these receptors is challenging beca...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aan3398
更新日期:2017-12-05 00:00:00
abstract::Over the last 50 years, the posttranslational modification (PTM) of proteins has emerged as a central mechanism for cells to regulate metabolism, growth, differentiation, cell-cell interactions, and immune responses. By influencing protein structure and function, PTM leads to a multiplication of proteome diversity. Re...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.290re7
更新日期:2009-09-29 00:00:00
abstract::A system-wide analysis of cell signaling requires detecting and quantifying many different proteins and their posttranslational modification states in the same cellular sample. Here, we present Protocols for two miniaturized, array-based methods, one of which provides detailed information on a central signaling protei...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2002372
更新日期:2012-01-10 00:00:00
abstract::Secretory cells, such as pancreatic beta cells, face the challenge of increasing protein synthesis severalfold during acute or chronic stimulation. This poses a burden on the endoplasmic reticulum (ER), the organelle where proinsulin synthesis and folding takes place. Thus, beta cells use various adaptive mechanisms t...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.3110pe7
更新日期:2010-02-23 00:00:00
abstract::Microglia mediate neuroprotection and neuropathogenesis but have not been directly associated with behavior. As gatekeepers of the brain's immune system, microglia protect the brain from pathogens but also contribute to inflammation, which may negatively affect neurons. A recent study demonstrates a role for Hoxb8-exp...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.3147jc8
更新日期:2010-11-09 00:00:00
abstract::Antigen-mediated stimulation of the T cell receptor (TCR) triggers activation of nuclear factor κB (NF-κB), a key transcriptional regulator of T cell proliferation and effector cell differentiation. TCR signaling to NF-κB requires both the Carma1-Bcl10-Malt1 (CBM) complex and the inhibitor of κB (IκB) kinase (IKK) com...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2004882
更新日期:2014-05-13 00:00:00
abstract::The CXC chemokine CXCL12 mediates the chemoattraction of T cells and enhances the stimulation of T cells through the T cell receptor (TCR). The adaptor SLP-76 [Src homology 2 (SH2) domain-containing leukocyte protein of 76 kD] has two key tyrosine residues, Tyr(113) and Tyr(128), that mediate signaling downstream of t...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2004018
更新日期:2013-07-30 00:00:00
abstract::Oxygen sensing by the carotid body is essential in vertebrates to adapt to reduced arterial oxygen tension. In this issue of Science Signaling, Yuan et al. report an intricate signaling system to transduce a physical parameter--oxygen tension--into a biological cellular signal (neural discharge) through changes in the...
journal_title:Science signaling
pub_type: 评论,杂志文章
doi:10.1126/scisignal.aab1665
更新日期:2015-04-21 00:00:00
abstract::Parkinson's disease (PD) is a neurodegenerative disorder in which the loss of dopaminergic neurons in the midbrain (mDA neurons) causes progressive loss of motor control and function. Using embryonic and mDA neurons, midbrain tissue from mice, and differentiated human neural stem cells, we investigated the mechanisms ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aal4165
更新日期:2017-08-22 00:00:00
abstract::Multicellular organisms rely on complex, fine-tuned protein networks to respond to environmental changes. We used in vitro evolution to explore the role of domain mutation and expansion in the evolution of network complexity. Using random mutagenesis to facilitate family expansion, we asked how versatile and robust th...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2000416
更新日期:2009-09-08 00:00:00
abstract::Although many anticancer drugs that target receptor tyrosine kinases (RTKs) provide clinical benefit, their long-term use is limited by resistance that is often attributed to increased abundance or activation of another RTK that compensates for the inhibited receptor. To uncover common and unique features in the signa...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2003994
更新日期:2013-07-16 00:00:00
abstract::The trimeric intracellular cation (TRIC) channels TRIC-A and TRIC-B localize predominantly to the endoplasmic reticulum (ER) and likely support Ca(2+) release from intracellular stores by mediating cationic flux to maintain electrical neutrality. Deletion and point mutations in TRIC-B occur in families with autosomal ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aad9055
更新日期:2016-05-17 00:00:00