Engineered calmodulins reveal the unexpected eminence of Ca2+ channel inactivation in controlling heart excitation.

Abstract:

:Engineered calmodulins (CaMs), rendered Ca2+-insensitive by mutations, function as dominant negatives in heterologous systems, and have revealed mechanisms of ion channel modulation by Ca2+/CaM. The use of these CaMs in native mammalian cells now emerges as a strategy to unmask the biology of such Ca2+ feedback. Here, we developed recombinant adenoviruses bearing engineered CaMs to facilitate their expression in adult heart cells, where Ca2+ regulation may be essential for moment-to-moment control of the heartbeat. Engineered CaMs not only eliminated the Ca2+-dependent inactivation of native calcium channels, but exposed an unexpectedly large impact of removing such feedback: the unprecedented (4- to 5-fold) prolongation of action potentials. This striking result recasts the basic paradigm for action-potential control and illustrates the promise of virally delivered engineered CaM to investigate the biology of numerous other CaM-signaling pathways.

authors

Alseikhan BA,DeMaria CD,Colecraft HM,Yue DT

doi

10.1073/pnas.262372999

keywords:

subject

Has Abstract

pub_date

2002-12-24 00:00:00

pages

17185-90

issue

26

eissn

0027-8424

issn

1091-6490

pii

262372999

journal_volume

99

pub_type

杂志文章
  • IgE receptor-positive non-B/non-T cells dominate the production of interleukin 4 and interleukin 6 in immunized mice.

    abstract::The phenotype and antigenic specificity of cells secreting interleukin (IL) 4, IL-6, and interferon gamma was studied in mice during primary and secondary immune responses. T lymphocytes were the major source of interferon gamma, whereas non-B/non-T cells were the dominant source of IL-4 and IL-6 in the spleens of imm...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.7.2534

    authors: Aoki I,Kinzer C,Shirai A,Paul WE,Klinman DM

    更新日期:1995-03-28 00:00:00

  • Hox5 genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion.

    abstract::Hox5 genes (Hoxa5, Hoxb5, Hoxc5) are exclusively expressed in the lung mesenchyme during embryogenesis, and the most severe phenotypes result from constitutive loss of function of all three genes. Because Hox5 triple null mutants exhibit perinatal lethality, the contribution of this paralogous group to postembryonic l...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1807067115

    authors: Hrycaj SM,Marty-Santos L,Cebrian C,Rasky AJ,Ptaschinski C,Lukacs NW,Wellik DM

    更新日期:2018-11-06 00:00:00

  • Reciprocity and behavioral heterogeneity govern the stability of social networks.

    abstract::The dynamics of social networks can determine the transmission of information, the spread of diseases, and the evolution of behavior. Despite this broad importance, a general framework for predicting social network stability has not been proposed. Here we present longitudinal data on the social dynamics of a cooperati...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1913284117

    authors: Dakin R,Ryder TB

    更新日期:2020-02-11 00:00:00

  • Brain white matter structure and COMT gene are linked to second-language learning in adults.

    abstract::Adult human brains retain the capacity to undergo tissue reorganization during second-language learning. Brain-imaging studies show a relationship between neuroanatomical properties and learning for adults exposed to a second language. However, the role of genetic factors in this relationship has not been investigated...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1606602113

    authors: Mamiya PC,Richards TL,Coe BP,Eichler EE,Kuhl PK

    更新日期:2016-06-28 00:00:00

  • Seed exchange networks, ethnicity, and sorghum diversity.

    abstract::Recent studies investigating the relationship between crop genetic diversity and human cultural diversity patterns showed that seed exchanges are embedded in farmers' social organization. However, our understanding of the social processes involved remains limited. We investigated how farmers' membership in three major...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1513238112

    authors: Labeyrie V,Thomas M,Muthamia ZK,Leclerc C

    更新日期:2016-01-05 00:00:00

  • RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex.

    abstract::Rapamycin is a potent immunosuppressant that blocks the G1/S transition in antigen-activated T cells and in yeast. The similar effects of rapamycin in animal cells and yeast suggest that the biochemical steps affected by rapamycin are conserved. Using a two-hybrid system we isolated mammalian clones that interact with...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.91.26.12574

    authors: Chiu MI,Katz H,Berlin V

    更新日期:1994-12-20 00:00:00

  • A neural substrate in the human hippocampus for linking successive events.

    abstract::Memory formation requires the placement of experienced events in the same order in which they appeared. A large body of evidence from human studies indicates that structures in the medial temporal lobe are critically involved in forming and maintaining such memories, and complementing evidence from lesion and electrop...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0910834107

    authors: Paz R,Gelbard-Sagiv H,Mukamel R,Harel M,Malach R,Fried I

    更新日期:2010-03-30 00:00:00

  • The Arf GTPase-activating protein ASAP1 regulates the actin cytoskeleton.

    abstract::Arf family GTP-binding proteins are best characterized as regulators of membrane traffic, but recent studies indicate an additional role in cytoskeletal organization. An Arf GTPase-activating protein of the centaurin beta family, ASAP1 (also known as centaurin beta4), binds Arf and two other known regulators of the ac...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.070552297

    authors: Randazzo PA,Andrade J,Miura K,Brown MT,Long YQ,Stauffer S,Roller P,Cooper JA

    更新日期:2000-04-11 00:00:00

  • Establishment of a cell line from lepidopteran wing imaginal discs: Induction of newly synthesized proteins by 20-hydroxyecdysone.

    abstract::A cell line has been developed from the imaginal wing discs of the lepidopteran insect Trichoplusia ni (Hübner). The cells grow in suspension as fluid-filled, multicellular vesicles. The cell line has been designated IAL-TND1. Two-dimensional electrophoresis (isoelectric focusing and sodium dodecyl sulfate/polyacrylam...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.79.8.2589

    authors: Lynn DE,Miller SG,Oberlander H

    更新日期:1982-04-01 00:00:00

  • Na,K-ATPase transport from endoplasmic reticulum to Golgi requires the Golgi spectrin-ankyrin G119 skeleton in Madin Darby canine kidney cells.

    abstract::Spectrin (betaISigma*) and ankyrin (AnkG119) associate with Golgi membranes and the dynactin complex, but their role in vesicle trafficking remains uncertain. We find that the actin-binding domain and membrane-association domain 1 (MAD1) of betaI spectrin together form a constitutive Golgi targeting signal in transfec...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.20.10711

    authors: Devarajan P,Stabach PR,De Matteis MA,Morrow JS

    更新日期:1997-09-30 00:00:00

  • Vitellogenin, juvenile hormone, insulin signaling, and queen honey bee longevity.

    abstract::In most animals, longevity is achieved at the expense of fertility, but queen honey bees do not show this tradeoff. Queens are both long-lived and fertile, whereas workers, derived from the same genome, are both relatively short-lived and normally sterile. It has been suggested, on the basis of results from workers, t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0701909104

    authors: Corona M,Velarde RA,Remolina S,Moran-Lauter A,Wang Y,Hughes KA,Robinson GE

    更新日期:2007-04-24 00:00:00

  • Increasing cAMP attenuates activation of mitogen-activated protein kinase.

    abstract::Activation of the mitogen-activated protein kinase (MAP kinase) isoforms ERK1 and ERK2 was investigated in rat adipocytes. Kinase activities were measured by using myelin basic protein as substrate after the isoforms were resolved by Mono Q chromatography or by immunoprecipitation with specific antibodies. Insulin inc...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.21.10305

    authors: Sevetson BR,Kong X,Lawrence JC Jr

    更新日期:1993-11-01 00:00:00

  • Novel human DNA alkyltransferases obtained by random substitution and genetic selection in bacteria.

    abstract::DNA repair alkyltransferases protect organisms against the cytotoxic, mutagenic, and carcinogenic effects of alkylating agents by transferring alkyl adducts from DNA to an active cysteine on the protein, thereby restoring the native DNA structure. We used random sequence substitutions to gain structure-function inform...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.12.6124

    authors: Christians FC,Loeb LA

    更新日期:1996-06-11 00:00:00

  • Quantitative MS-based enzymology of caspases reveals distinct protein substrate specificities, hierarchies, and cellular roles.

    abstract::Proteases constitute the largest enzyme family, yet their biological roles are obscured by our rudimentary understanding of their cellular substrates. There are 12 human caspases that play crucial roles in inflammation and cell differentiation and drive the terminal stages of cell death. Recent N-terminomics technolog...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1524900113

    authors: Julien O,Zhuang M,Wiita AP,O'Donoghue AJ,Knudsen GM,Craik CS,Wells JA

    更新日期:2016-04-05 00:00:00

  • Deficiency of Aph1B/C-gamma-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment.

    abstract::Regulated intramembrane proteolysis by gamma-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different gamma-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0800507105

    authors: Dejaegere T,Serneels L,Schäfer MK,Van Biervliet J,Horré K,Depboylu C,Alvarez-Fischer D,Herreman A,Willem M,Haass C,Höglinger GU,D'Hooge R,De Strooper B

    更新日期:2008-07-15 00:00:00

  • Virstatin inhibits dimerization of the transcriptional activator ToxT.

    abstract::The development of antimicrobials is critical in this time of increasing antibiotic resistance of most clinically relevant bacteria. To date, all current antibiotics focus on inhibiting crucial enzymatic activities of their protein targets (i.e., trimethoprim for dihydrofolate reductase), thus disrupting in vitro esse...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0611643104

    authors: Shakhnovich EA,Hung DT,Pierson E,Lee K,Mekalanos JJ

    更新日期:2007-02-13 00:00:00

  • Transgenic study of parallelism in plant morphological evolution.

    abstract::Developmental constraint is indicated when one finds that similar genetic mechanisms are responsible for independent origins of the same derived phenotype. We studied three independent origins of rosette flowering within the mustard family and attempted to evaluate the extent to which the same mechanisms were involved...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0401824101

    authors: Yoon HS,Baum DA

    更新日期:2004-04-27 00:00:00

  • Interkingdom metabolic transformations captured by microbial imaging mass spectrometry.

    abstract::In polymicrobial infections, microbes can interact with both the host immune system and one another through direct contact or the secretion of metabolites, affecting disease progression and treatment options. The thick mucus in the lungs of patients with cystic fibrosis is highly susceptible to polymicrobial infection...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1206855109

    authors: Moree WJ,Phelan VV,Wu CH,Bandeira N,Cornett DS,Duggan BM,Dorrestein PC

    更新日期:2012-08-21 00:00:00

  • Pausing and premature termination of human RNA polymerase II during transcription of adenovirus in vivo and in vitro.

    abstract::The major late transcriptional unit of adenovirus type 2 has served as a model for studying transcription in eukaryotes. We report that pausing and premature termination are intrinsic to the transcription of this transcriptional unit by RNA polymerase II. In vivo and in isolated nuclei, transcription pauses at discret...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.19.5931

    authors: Maderious A,Chen-Kiang S

    更新日期:1984-10-01 00:00:00

  • In situ structural studies of tripeptidyl peptidase II (TPPII) reveal spatial association with proteasomes.

    abstract::Tripeptidyl peptidase II (TPPII) is a eukaryotic protease acting downstream of the 26S proteasome; it removes tripeptides from the degradation products released by the proteasome. Structural studies in vitro have revealed the basic architecture of TPPII, a two-stranded linear polymer that assembles to form a spindle-s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1701367114

    authors: Fukuda Y,Beck F,Plitzko JM,Baumeister W

    更新日期:2017-04-25 00:00:00

  • Spontaneous voice-face identity matching by rhesus monkeys for familiar conspecifics and humans.

    abstract::Recognition of a particular individual occurs when we reactivate links between current perceptual inputs and the previously formed representation of that person. This recognition can be achieved by identifying, separately or simultaneously, distinct elements such as the face, silhouette, or voice as belonging to one i...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1008169108

    authors: Sliwa J,Duhamel JR,Pascalis O,Wirth S

    更新日期:2011-01-25 00:00:00

  • A thermodynamic framework for Mg2+ binding to RNA.

    abstract::We present a model describing how Mg(2+) binds and stabilizes specific RNA structures. In this model, RNA stabilization arises from two energetically distinct modes of Mg(2+) binding: diffuse- and site-binding. Diffusely bound Mg(2+) are electrostatically attracted to the strong anionic field around the RNA and are ac...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.221234598

    authors: Misra VK,Draper DE

    更新日期:2001-10-23 00:00:00

  • Molecular specialization of breast vasculature: a breast-homing phage-displayed peptide binds to aminopeptidase P in breast vasculature.

    abstract::In vivo phage display identifies peptides that selectively home to the vasculature of individual organs, tissues, and tumors. Here we report the identification of a cyclic nonapeptide, CPGPEGAGC, which homes to normal breast tissue with a 100-fold selectivity over nontargeted phage. The homing of the phage is inhibite...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.251687998

    authors: Essler M,Ruoslahti E

    更新日期:2002-02-19 00:00:00

  • TMEM203 is a binding partner and regulator of STING-mediated inflammatory signaling in macrophages.

    abstract::Regulation of IFN signaling is critical in host recognition and response to pathogens while its dysregulation underlies the pathogenesis of several chronic diseases. STimulator of IFN Genes (STING) has been identified as a critical mediator of IFN inducing innate immune pathways, but little is known about direct coreg...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1901090116

    authors: Li Y,James SJ,Wyllie DH,Wynne C,Czibula A,Bukhari A,Pye K,Bte Mustafah SM,Fajka-Boja R,Szabo E,Angyal A,Hegedus Z,Kovacs L,Hill AVS,Jefferies CA,Wilson HL,Yongliang Z,Kiss-Toth E

    更新日期:2019-08-13 00:00:00

  • Saposin A: second cerebrosidase activator protein.

    abstract::Saposin A, a heat-stable 16-kDa glycoprotein, was isolated from Gaucher disease spleen and purified to homogeneity. Chemical sequencing from its amino terminus and of peptides obtained by digestion with protease from Staphylococcus aureus strain V-8 demonstrated that saposin A is derived from proteolytic processing of...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.9.3389

    authors: Morimoto S,Martin BM,Yamamoto Y,Kretz KA,O'Brien JS,Kishimoto Y

    更新日期:1989-05-01 00:00:00

  • Invariable stoichiometry of ribosomal proteins in mouse brain tissues with aging.

    abstract::Across phyla, the ribosomes-the central molecular machines for translation of genetic information-exhibit an overall preserved architecture and a conserved functional core. The natural heterogeneity of the ribosome periodically phases a debate on their functional specialization and the tissue-specific variations of th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1912060116

    authors: Amirbeigiarab S,Kiani P,Velazquez Sanchez A,Krisp C,Kazantsev A,Fester L,Schlüter H,Ignatova Z

    更新日期:2019-11-05 00:00:00

  • Energy transfer between photosystem II units in a connected package model of the photochemical apparatus of photosynthesis.

    abstract::A model of the photochemical apparatus of photosynthesis, presented previously in a tripartite format, is used in a bipartite format to analyze energy transfer between photosystem II units. The model is used to develop analytical expressions for the photochemical properties of chloroplasts that include a term for the ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.8.4697

    authors: Butler WL

    更新日期:1980-08-01 00:00:00

  • De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis.

    abstract::Most transmissible spongiform encephalopathies arise either spontaneously or by infection. Mutations of PRNP, which encodes the prion protein, PrP, segregate with phenotypically similar diseases. Here we report that moderate overexpression in transgenic mice of mPrP(170N,174T), a mouse PrP with two point mutations tha...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0810680105

    authors: Sigurdson CJ,Nilsson KP,Hornemann S,Heikenwalder M,Manco G,Schwarz P,Ott D,Rülicke T,Liberski PP,Julius C,Falsig J,Stitz L,Wüthrich K,Aguzzi A

    更新日期:2009-01-06 00:00:00

  • Different functional boundaries for the major antigenic region of two cytochromes c.

    abstract::The antigenic sites of horse and rat cytochromes c in the major antigenic region were compared using a panel of variant cytochromes c and a large number of BALB/c mouse monoclonal antibodies (mAbs) in competitive ELISAs. The major antigenic region of cytochrome c is located on the surface opposite of that containing t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.10.4428

    authors: Jemmerson R,Johnson JG

    更新日期:1991-05-15 00:00:00

  • Eradication of large colon tumor xenografts by targeted delivery of maytansinoids.

    abstract::The maytansinoid drug DM1 is 100- to 1000-fold more cytotoxic than anticancer drugs that are currently in clinical use. The immunoconjugate C242-DM1 was prepared by conjugating DM1 to the monoclonal antibody C242, which recognizes a mucin-type glycoprotein expressed to various extents by human colorectal cancers. C242...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.16.8618

    authors: Liu C,Tadayoni BM,Bourret LA,Mattocks KM,Derr SM,Widdison WC,Kedersha NL,Ariniello PD,Goldmacher VS,Lambert JM,Blättler WA,Chari RV

    更新日期:1996-08-06 00:00:00