Abstract:
:Excessive activation of calmodulin kinase II (CaMKII) causes arrhythmias and heart failure, but the cellular mechanisms for CaMKII-targeted proteins causing disordered cell membrane excitability and myocardial dysfunction remain uncertain. Failing human cardiomyocytes exhibit increased CaMKII and voltage-gated Ca(2+) channel (Ca(V)1.2) activity, and enhanced expression of a specific Ca(V)1.2 beta-subunit protein isoform (beta(2a)). We recently identified Ca(V)1.2 beta(2a) residues critical for CaMKII phosphorylation (Thr 498) and binding (Leu 493), suggesting the hypothesis that these amino acids are crucial for cardiomyopathic consequences of CaMKII signaling. Here we show WT beta(2a) expression causes cellular Ca(2+) overload, arrhythmia-triggering cell membrane potential oscillations called early afterdepolarizations (EADs), and premature death in paced adult rabbit ventricular myocytes. Prevention of intracellular Ca(2+) release by ryanodine or global cellular CaMKII inhibition reduced EADs and improved cell survival to control levels in WT beta(2a)-expressing ventricular myocytes. In contrast, expression of beta(2a) T498A or L493A mutants mimicked the protective effects of ryanodine or global cellular CaMKII inhibition by reducing Ca(2+) entry through Ca(V)1.2 and inhibiting EADs. Furthermore, Ca(V)1.2 currents recorded from cells overexpressing CaMKII phosphorylation- or binding-incompetent beta(2a) subunits were incapable of entering a CaMKII-dependent high-activity gating mode (mode 2), indicating that beta(2a) Thr 498 and Leu 493 are required for Ca(V)1.2 activation by CaMKII in native cells. These data show that CaMKII binding and phosphorylation sites on beta(2a) are concise but pivotal components of a molecular and biophysical and mechanism for EADs and impaired survival in adult cardiomyocytes.
journal_name
Proc Natl Acad Sci U S Aauthors
Koval OM,Guan X,Wu Y,Joiner ML,Gao Z,Chen B,Grumbach IM,Luczak ED,Colbran RJ,Song LS,Hund TJ,Mohler PJ,Anderson MEdoi
10.1073/pnas.0913760107subject
Has Abstractpub_date
2010-03-16 00:00:00pages
4996-5000issue
11eissn
0027-8424issn
1091-6490pii
0913760107journal_volume
107pub_type
杂志文章abstract::Cell-mediated immunity is critical for host resistance to tuberculosis. T lymphocytes recognizing antigens presented by the major histocompatibility complex (MHC) class I and class II molecules have been found to be necessary for control of mycobacterial infection. Mice genetically deficient in the generation of MHC c...
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.96.26.15190
更新日期:1999-12-21 00:00:00
abstract::The modern Old World Monkeys (Superfamily Cercopithecoidea, Family Cercopithecidae) can be traced back into the late Miocene, but their origin and subsequent diversification is obscured by the scarcity of terrestrial fossil sites in Africa between 15 and 6 Ma. Here, we document the presence of cercopithecids at 12.5 M...
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.1213691110
更新日期:2013-04-09 00:00:00
abstract::Migration of organisms (or cells) is typically an adaptive response to spatiotemporal variation in resources that requires individuals to detect and respond to long-range and noisy environmental gradients. Many organisms, from wildebeest to bacteria, migrate en masse in a process that can involve a vast number of indi...
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.1006874107
更新日期:2010-09-14 00:00:00
abstract::Early passages of NIH 3T3 cells yield about 10 transformed foci for every 10(5) cells seeded after the cells multiply to confluence in a standardized 2-week assay. The question arose whether more cells would give rise to foci if given more time for their development. This question could not be answered simply by exten...
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.91.2.599
更新日期:1994-01-18 00:00:00
abstract::Plants frequently respond to herbivorous insect attack by synthesizing defense proteins that deter insect feeding and prevent additional herbivory. Maize (Zea mays L.) lines, resistant to feeding by a number of lepidopteran species, rapidly mobilize a unique 33-kDa cysteine protease in response to caterpillar feeding....
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.202224899
更新日期:2002-10-01 00:00:00
abstract::Insig-1 and -2 are closely related proteins of the endoplasmic reticulum (ER) that block proteolytic activation of sterol regulatory element-binding proteins (SREBPs), transcription factors that activate the synthesis of cholesterol and fatty acids in liver and other organs. When cellular cholesterol levels are high, ...
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.0130116100
更新日期:2003-03-18 00:00:00
abstract::The sensitive and accurate quantification of protein biomarkers plays important roles in clinical diagnostics and biomedical research. Sandwich ELISA and its variants accomplish the capture and detection of a target protein via two antibodies that tightly bind at least two distinct epitopes of the same antigen and hav...
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.2008312117
更新日期:2020-09-15 00:00:00
abstract::"Evolution behaves like a tinkerer" (François Jacob, Science, 1977). Software systems provide a singular opportunity to understand biological processes using concepts from network theory. The Debian GNU/Linux operating system allows us to explore the evolution of a complex network in a unique way. The modular design d...
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.1115960108
更新日期:2011-12-13 00:00:00
abstract::It is unknown whether cross-regulatory interactions between homeotic genes, which have been shown to play an important role in the maintenance of their expression domains during Drosophila development, are also important during mammalian development. We have analyzed here the expression of Hox genes in Hoxa-1 (Hox-1.6...
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.90.16.7666
更新日期:1993-08-15 00:00:00
abstract::We have isolated overlapping phage genomic clones covering an area of 26 kilobases that encodes the human alpha 2-plasmin inhibitor. The alpha 2-plasmin inhibitor gene contains 10 exons and 9 introns distributed over approximately 16 kilobases of DNA. To our knowledge, the number of introns is the highest yet reported...
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.85.18.6836
更新日期:1988-09-01 00:00:00
abstract::The AML1 gene, located on chromosome 21, is involved in several distinct chromosomal translocations in human leukemia. In t(8;21) acute myelogenous leukemia (AML), the AML1 gene is juxtaposed to the ETO gene located on chromosome 8, generating an AML1/ETO fusion protein. Both AML1/ETO and the AML1 proteins recognize 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.93.24.14059
更新日期:1996-11-26 00:00:00
abstract::To determine the importance of the thrombin substrate recognition exosite for fibrinogen binding in the formation of both arterial and venous thrombi, we evaluated the antithrombotic effects of the tyrosine-sulfated dodecapeptide from residues 53-64 of hirudin (H peptide) in a nonhuman primate model. This peptide was ...
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.88.4.1177
更新日期:1991-02-15 00:00:00
abstract::Type I (IFN-alpha/beta) and type III (IFN-lambdas) IFNs are important components of the host antiviral response. Although type III IFNs possess intrinsic antiviral activity similar to that of type I IFNs, they signal through a specific unique receptor complex, and their functional importance for antiviral resistance 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.0610352104
更新日期:2007-06-05 00:00:00
abstract::Three allelic variants of P-pilus-associated G-adhesins (lectins) with different cell-binding properties were recently described. Here we have analyzed Escherichia coli HB101 strains expressing the recombinant G-adhesin variants for their ability to agglutinate erythrocytes from various species as this relates to 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.88.20.9340
更新日期:1991-10-15 00:00:00
abstract::Methane emissions due to accidents in the oil and natural gas sector are very challenging to monitor, and hence are seldom considered in emission inventories and reporting. One of the main reasons is the lack of measurements during such events. Here we report the detection of large methane emissions from a gas well bl...
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.1908712116
更新日期:2019-12-16 00:00:00
abstract::Because of the insolubility and polymeric properties of amyloid fibrils, techniques used conventionally to analyze protein structure and dynamics have often been hampered. Ultrasonication can induce the monomeric solution of amyloidogenic proteins to form amyloid fibrils. However, ultrasonication can break down prefor...
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.0901422106
更新日期:2009-07-07 00:00:00
abstract::Retinopathy of prematurity is a blinding disease, initiated by lack of retinal vascular growth after premature birth. We show that lack of insulin-like growth factor I (IGF-I) in knockout mice prevents normal retinal vascular growth, despite the presence of vascular endothelial growth factor, important to vessel devel...
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.101113998
更新日期:2001-05-08 00:00:00
abstract::Individual proteins can now often be modified with atomic precision, but there are still major obstacles to connecting proteins into larger assemblies. To direct protein assembly, ideally, peptide tags would be used, providing the minimal perturbation to protein function. However, binding to peptides is generally weak...
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.1315776111
更新日期:2014-04-01 00:00:00
abstract::Brain src protooncogene is expressed in two forms, one identical to message in other tissues, and one containing an 18-nucleotide insert specific to brain. We have mapped mRNA for the two forms of src in rat brain with selective antisense oligonucleotide probes to the brain (src+) and peripheral (src-) forms. Fetal ra...
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.85.24.9831
更新日期:1988-12-01 00:00:00
abstract::We have selected from a mixture of random polynucleotides an RNA that is able to replicate in the presence of the DNA-dependent RNA polymerase of Escherichia coli, provided the medium contains Mn(2+) and ITP, in addition to ATP, CTP, and UTP. The RNA consists of a chain of about 125 (+/-25) nucleotides and appears to ...
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.70.3.934
更新日期:1973-03-01 00:00:00
abstract::The papain-solubilized fragment of the heavy chain of HLA-B7, which is the NH2-terminal part of the whole polypeptide chain, can be divided into three regions by mild acid and cyanogen bromide cleavages. The first 100 amino acids terminating in a methionine residue contain the carbohydrate moiety; this segment is foll...
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.74.9.4002
更新日期:1977-09-01 00:00:00
abstract::The ability of the cornea to transmit light while being mechanically resilient is directly attributable to the formation of an extracellular matrix containing orthogonal sheets of collagen fibrils. The detailed structure of the fibrils and how this structure underpins the mechanical properties and organization of 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.111150598
更新日期:2001-06-19 00:00:00
abstract::We have used a motif-based structural search method to identify structural homologs of the hormone binding domains of the nuclear receptors from among a set of known protein structures and have found the closest similarity with members of the subtilisin-like serine proteases. These proteins consist of an open twisted ...
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.90.21.9949
更新日期:1993-11-01 00:00:00
abstract::A lysine-to-arginine substitution at amino acid 65 (K65R) in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is associated with resistance to 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI), and the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine (3TC). To further characterize the molecu...
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.92.7.2760
更新日期:1995-03-28 00:00:00
abstract::Amplitude-modulated phosphorescence/microwave double-resonance (AM-PMDR) spectra are reported for complexes of methylmercury(II) cation, designated CH3Hg(II), with tryptophan and glyceraldehyde-3-phosphate dehydrogenase (GPDHase; from rabbit muscle). Wavelength shifts are observed in the AM-PMDR spectra of CH3Hg(II)-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.79.14.4313
更新日期:1982-07-01 00:00:00
abstract::Alphavirus envelope proteins, organized as trimers of E2-E1 heterodimers on the surface of the pathogenic alphavirus, mediate the low pH-triggered fusion of viral and endosomal membranes in human cells. The lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches...
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.1414190112
更新日期:2015-02-17 00:00:00
abstract::The helical ribosome structures of Mycoplasma gallisepticum have been analyzed by optical diffraction and the rotational symmetry technique. The helix repeat (510 A) is composed of 10 ribosomes in 3 turns. The rotational studies show some ribosome fine structure. ...
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.68.1.43
更新日期:1971-01-01 00:00:00
abstract::Electrical stimulation of the cervical vagus nerve in anesthetized guinea pigs induced a rapid increase in respiratory insufflation pressure, suggesting increased airway resistance. After intravenous administration of a substance P (SP) antagonist, [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]SP, the insufflation pressure re...
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.80.4.1120
更新日期:1983-02-01 00:00:00
abstract::Whole human blood was examined by (31)P nuclear magnetic resonance spectroscopy. Individual phosphates (alpha,beta,gamma) of ATP were identifiable, and two microenvironments appeared to be present for this molecule. When sequential recordings of freshly collected blood were made, 2,3-diphosphoglycerate was observed to...
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.71.6.2487
更新日期:1974-06-01 00:00:00
abstract::Herpesviruses are dsDNA viruses, but their virions may additionally contain RNAs that can be transduced to recipient cells. The biological functions of herpes virion RNA species are unknown. Here we address this issue for EBV, a widespread human herpesvirus with oncogenic potential. We show that EBV-derived particles ...
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.1115906109
更新日期:2012-05-22 00:00:00