Abstract:
:Activation of P2X2 receptor channels by extracellular ATP is thought to play important roles in cochlear adaptation to elevated sound levels and protection from overstimulation. Each subunit of a trimeric P2X2 receptor is composed of intracellular N and C termini, a large extracellular domain containing the ATP binding site and 2 transmembrane helices (TM1 and TM2) that form a cation permeable pore. Whole-exome sequencing and linkage analysis have identified 3 hP2X2 receptor mutations (V60L, D273Y, and G353R) that cause dominantly inherited progressive sensorineural hearing loss (DFNA41). Available structures of related P2X receptors suggest that these 3 mutations localize to TM1 (V60L), TM2 (G353R), or the β-sheet linking the TMs to the extracellular ATP binding sites (D273Y). Previous studies have concluded that the V60L and G353R mutants are nonfunctional, whereas the D273Y mutant has yet to be studied. Here, we demonstrate that both V60L and G353R mutations do form functional channels, whereas the D273Y mutation prevents the expression of functional channels on the cell membrane. Our results show that the V60L mutant forms constitutively active channels that are insensitive to ATP or the antagonist suramin, suggesting uncoupling of the pore and the ligand binding domains. In contrast, the G353R mutant can be activated by ATP but exhibits alterations in sensitivity to ATP, inward rectification, and ion selectivity. Collectively, our results demonstrate that the loss of functional P2X2 receptors or distinct alterations of its functional properties lead to noise-induced hearing loss, highlighting the importance of these channels in preserving hearing.
journal_name
Proc Natl Acad Sci U S Aauthors
George B,Swartz KJ,Li Mdoi
10.1073/pnas.1912156116subject
Has Abstractpub_date
2019-11-05 00:00:00pages
22862-22871issue
45eissn
0027-8424issn
1091-6490pii
1912156116journal_volume
116pub_type
杂志文章abstract::Chylomicron catabolism is known to be initiated by the enzyme lipoprotein lipase (triacylglycero-protein acylhydrolase, EC 3.1.1.34). Chylomicron remnants, produced by lipolysis, are rapidly taken up by the liver via an apolipoprotein E (apoE)-mediated, receptor-dependent process. The low density lipoprotein (LDL) rec...
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.88.19.8342
更新日期:1991-10-01 00:00:00
abstract::Current evidence suggests that the length of poly(A) tails of bacterial mRNAs result from a competition between poly(A) polymerase and exoribonucleases that attack the 3' ends of RNAs. Here, we show that host factor Hfq is also involved in poly(A) tail metabolism. Inactivation of the hfq gene reduces the length of pol...
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.040549897
更新日期:2000-02-15 00:00:00
abstract::The in vitro biological activities of several rabies virus-neutralizing monoclonal antibodies (mAbs) were compared with their ability to prevent a lethal rabies virus encephalomyelitis. The protective activity of a particular mAb in vivo did not correlate with its virus-neutralizing activity in vitro; rather it was 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.89.15.7252
更新日期:1992-08-01 00:00:00
abstract::Mutants of Arabidopsis that contain reduced levels of polyunsaturated fatty acids showed growth characteristics at 22 degrees C that were very similar to wild type. By contrast, at 12 degrees C, the mutants failed to undergo stem elongation during reproductive growth although they produced normal flowers and fertile 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.90.13.6208
更新日期:1993-07-01 00:00:00
abstract::While the general structure of immunoglobulin chains has remained relatively unchanged throughout evolution, the organization of the genes encoding these molecules differs substantially. To understand how the rearranging immunoglobulin system arose, it is necessary to examine living representatives of the most early v...
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.90.21.9882
更新日期:1993-11-01 00:00:00
abstract::Two continuous-suspension lymphocyte lines were isolated from the spleen and fibrosarcoma of a New Zealand Black female mouse. A C-type virus with a density of 1.16 g x cm(-3), 70S RNA, and RNA-directed DNA polymerase activity was isolated. The virus was infectious for NRK, NZB, (NZB x NZW)F(1), and (NZW x NZW)F(1) em...
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.69.10.2965
更新日期:1972-10-01 00:00:00
abstract::The amount of extra-pair paternity in socially monogamous bird species varies from 0% to 76% extra-pair offspring. The causes of this remarkable interspecific variation are largely unknown, although intraspecific analyses suggest that females seek extra-pair matings to improve the genetic quality of their offspring. 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.95.16.9390
更新日期:1998-08-04 00:00:00
abstract::The question was addressed whether the risk of cancer of an individual in a heterogeneous population can be predicted on the basis of measurable biochemical and biological variables postulated to be associated with the process of chemical carcinogenesis. Using the skin tumor model with outbred male NMRI mice, the late...
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.92.13.5900
更新日期:1995-06-20 00:00:00
abstract::An oligoribonucleotide (a 27-mer) that mimics the sarcin/ricin (S/R) domain of Escherichia coli 23S rRNA binds elongation factor EF-G; the Kd is 6.9 microM, whereas for binding to ribosomes it is 0.7 microM. Binding saturates when EF-G and the S/R RNA are equimolar; at saturation 70% of the input RNA is in complexes w...
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.94.23.12280
更新日期:1997-11-11 00:00:00
abstract::When Sertoli cells of the seminiferous epithelium in the testis were cultured on Matrigel (a reconstituted basement membrane), laminin, or one of the biologically active laminin-derived peptides (YIGSR, SIKVAV, or RGD), they exhibited dramatic changes in morphology accompanied by changes in protein secretion and gene ...
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.91.15.7027
更新日期:1994-07-19 00:00:00
abstract::The nucleosomal repeat lengths of bulk chromatin and the chromatin of transcriptionally active and inactive genes were analyzed in two mouse cell lines and adult mouse spleens. The adult beta-globin gene exhibits a nucleosomal repeat length approximately 11 base pairs longer than (i) an inactive embryonic globin gene,...
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.80.18.5505
更新日期:1983-09-01 00:00:00
abstract::Glucagon-like peptide-1 (GLP-1), released from gut endocrine L cells in response to glucose, regulates appetite, insulin secretion, and gut motility. How glucose given orally, but not systemically, induces GLP-1 secretion is unknown. We show that human duodenal L cells express sweet taste receptors, the taste G protei...
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.0706890104
更新日期:2007-09-18 00:00:00
abstract::Phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) by cAMP-dependent protein kinase leads to chloride flux in epithelial cells. Is CFTR also required for the calcium-dependent activation of chloride channels? We used antisense oligodeoxynucleotides to CFTR to reduce the expression of CFT...
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.89.15.6785
更新日期:1992-08-01 00:00:00
abstract::Monoclonal antibodies have been obtained that recognize either the A or B chain of human urinary urokinase. These antibodies identify human urokinase-producing cells and the product of urokinase mRNA. Anti-urokinase monoclonal antibodies precipitate an approximately equal to 54,000-dalton protein synthesized in vitro ...
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.81.1.110
更新日期:1984-01-01 00:00:00
abstract::Social insects are promising new models in aging research. Within single colonies, longevity differences of several magnitudes exist that can be found elsewhere only between different species. Reproducing queens (and, in termites, also kings) can live for several decades, whereas sterile workers often have a lifespan ...
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.1804046115
更新日期:2018-05-22 00:00:00
abstract::We use the inverse scattering method to determine the weak limit of solutions of the Korteweg-deVries equation as dispersion tends to zero. The limit, valid for all time, is characterized in terms of a quadratic programming problem which can be solved with the aid of function theoretic methods. For large t, the soluti...
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.76.8.3602
更新日期:1979-08-01 00:00:00
abstract::This paper presents insights and action proposals to better harness technological innovation for sustainable development. We begin with three key insights from scholarship and practice. First, technological innovation processes do not follow a set sequence but rather emerge from complex adaptive systems involving many...
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.1525004113
更新日期:2016-08-30 00:00:00
abstract::The ability to instantly create a state of immunity as achieved in the passive transfer of hyperimmune globulin has had a tremendous impact on public health. Unlike passive immunization, active immunization, which is the foundation of vaccinology, is an anticipatory strategy with inherent limitations. Here we show 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.0900147106
更新日期:2009-03-17 00:00:00
abstract::p53 is a master regulatory, sequence-specific transcription factor that directly controls expression of over 100 genes in response to various stress signals. Transactivation is generally considered to occur through p53 binding to a consensus response element (RE) composed of two 5'-RRRCWWGYYY-3' decamers. Recently, st...
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.0909129107
更新日期:2010-01-26 00:00:00
abstract::Glaucoma is a common cause of vision loss or blindness and reduction of intraocular pressure (IOP) has been proven beneficial in a large fraction of glaucoma patients. The IOP is maintained by the trabecular meshwork (TM) and the elevation of IOP in open-angle glaucoma is associated with dysfunction and loss of the po...
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.1604153113
更新日期:2016-06-21 00:00:00
abstract::Hox genes encode transcription factors widely used for diversifying animal body plans in development and evolution. To achieve functional specificity, Hox proteins associate with PBC class proteins, Pre-B cell leukemia homeobox (Pbx) in vertebrates, and Extradenticle (Exd) in Drosophila, and were thought to use a uniq...
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.1006964108
更新日期:2011-02-08 00:00:00
abstract::The location of renin (EC 3.4.99.19) in rat pituitary was determined by the peroxidase-antiperoxidase immunohistochemical technique. By using antisera prepared with purified rat renal renin, an immunoreactive substance was localized within ovoid cells scattered throughout the anterior pituitary. These cells were shown...
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.78.12.7579
更新日期:1981-12-01 00:00:00
abstract::Arabidopsis has been popular as a model plant system for decades. Completion of the Arabidopsis genome and the availability of large expressed sequence-tag collections from other dicot species provides an opportunity to assess gene content in Arabidopsis, specifically by identifying genes from dicot test species that ...
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.142126599
更新日期:2002-07-09 00:00:00
abstract::Extragalactic X-ray surveys over the past decade have dramatically improved understanding of the majority populations of active galactic nuclei (AGNs) over most of the history of the universe. Here we briefly highlight some of the exciting discoveries about AGN demography, physics, and ecology, with a focus on results...
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.0914151107
更新日期:2010-04-20 00:00:00
abstract::Targeted ablation of the surfactant protein D (SP-D) gene caused chronic inflammation, emphysema, and fibrosis in the lungs of SP-D (-/-) mice. Although lung morphology was unperturbed during the first 2 weeks of life, airspace enlargement was observed by 3 weeks and progressed with advancing age. Inflammation consist...
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.100448997
更新日期:2000-05-23 00:00:00
abstract::Activation of the syk tyrosine kinase occurs almost immediately following engagement of many types of antigen receptors, including Fc receptors, but the mechanism through which syk is activated is currently unclear. Here we demonstrate that Fc receptor-induced syk activation occurs as the result of phosphorylation 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.94.5.1919
更新日期:1997-03-04 00:00:00
abstract::In biological processes, such as fission, fusion and trafficking, it has been shown that lipids of different shapes are sorted into regions with different membrane curvatures. This lipid sorting has been hypothesized to be due to the coupling between the membrane curvature and the lipid's spontaneous curvature, which ...
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.0907354106
更新日期:2009-12-29 00:00:00
abstract::Circular RNA replicons have been reported in plants and, in one case, in animal cells. We describe such an element in yeast. In certain yeast strains, a 20S RNA species appears on transfer of cells to acetate medium. This phenotype shows cytoplasmic (non-Mendelian) inheritance and the 20S RNA is associated with 23-kDa...
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.87.19.7628
更新日期:1990-10-01 00:00:00
abstract::Aspartic acid in the second transmembrane domain is a highly conserved amino acid among the G protein-coupled receptors and is functionally important for agonist binding and G-protein coupling in beta 2-adrenergic and luteinizing hormone receptors. To determine whether this aspartic acid is also involved in the functi...
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.90.11.5133
更新日期:1993-06-01 00:00:00
abstract::The calcium, calmodulin-dependent phosphatase calcineurin, regulates growth and gene expression of striated muscles. The activity of calcineurin is modulated by a family of cofactors, referred to as modulatory calcineurin-interacting proteins (MCIPs). In the heart, the MCIP1 gene is activated by calcineurin and has be...
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.0308723101
更新日期:2004-03-02 00:00:00