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• W2000702493 abstract "Small neurons of the dorsal root ganglia (DRG) are known to play an important role in nociceptive mechanisms. These neurons express two types of sodium current, which differ in their inactivation kinetics and sensitivity to tetrodotoxin. Here, we report the cloning of the α-subunit of a novel, voltage-gated sodium channel (PN3) from rat DRG. Functional expression in Xenopus oocytes showed that PN3 is a voltage-gated sodium channel with a depolarized activation potential, slow inactivation kinetics, and resistance to high concentrations of tetrodotoxin. In situ hybridization to rat DRG indicated that PN3 is expressed primarily in small sensory neurons of the peripheral nervous system. Small neurons of the dorsal root ganglia (DRG) are known to play an important role in nociceptive mechanisms. These neurons express two types of sodium current, which differ in their inactivation kinetics and sensitivity to tetrodotoxin. Here, we report the cloning of the α-subunit of a novel, voltage-gated sodium channel (PN3) from rat DRG. Functional expression in Xenopus oocytes showed that PN3 is a voltage-gated sodium channel with a depolarized activation potential, slow inactivation kinetics, and resistance to high concentrations of tetrodotoxin. In situ hybridization to rat DRG indicated that PN3 is expressed primarily in small sensory neurons of the peripheral nervous system. Voltage-gated sodium channels play a fundamental role in the regulation of neuronal excitability. In addition to differences in primary structure and kinetic properties(1.Catterall W.A. Physiol. Rev. 1992; 72: S15-S48Crossref PubMed Google Scholar), these channels can be distinguished pharmacologically on the basis of their relative sensitivity to the neurotoxin, tetrodotoxin (TTX)( 1The abbreviations used are: TTXtetrodotoxinDRGdorsal root ganglionPCRpolymerase chain reactionRTreverse transcriptionSCNβ1sodium channel β1-subunithhumanrrat.)(2.White J.A. Alonso A. Kay A.R. Neuron. 1993; 11: 1037-1047Abstract Full Text PDF PubMed Scopus (69) Google Scholar). Two types of sodium currents are expressed by sensory neurons within the dorsal root ganglion (DRG), a fast inactivating TTX-sensitive current and a slow inactivating, TTX-resistant current that appears to be expressed by a high proportion of the small afferent neurons(3.Kostyuk P.G. Veselovsky N.S. Tsyndrenko A.Y. Neuroscience. 1981; 6: 2423-2430Crossref PubMed Scopus (314) Google Scholar, 4.McLean M.J. Bennett P.B. Thomas R.M. Mol. Cell. Biochem. 1988; 80: 95-107PubMed Google Scholar, 5.Roy M.L. Narahashi T. J. Neurosci. 1992; 12: 2104-2111Crossref PubMed Google Scholar, 6.Caffrey J.M. Eng D.L. Black J.A. Waxman S.G. Kocsis J.D. Brain Res. 1992; 592: 283-297Crossref PubMed Scopus (268) Google Scholar, 7.Elliott A.A. Elliott J.R. J. Physiol. (Lond.). 1993; 463: 39-56Crossref Scopus (383) Google Scholar, 8.Ogata N. Tatebayashi H. J. Physiol. (Lond.). 1993; 466: 9-37Google Scholar). Of the large and small neurons of the DRG, the latter is of primary importance in the processing of nociceptive information within the somatosensory system(9.Coderre T.J. Katz J. Vaccarino A.L. Melzack R. Pain. 1993; 52: 259-285Abstract Full Text PDF PubMed Scopus (1764) Google Scholar, 10.Woolf C.J. Doubell T.P. Curr. Opin. Neurobiol. 1994; 4: 525-534Crossref PubMed Scopus (338) Google Scholar). In order to define the molecular basis of sodium channel conductance in sensory neurons, we have attempted to identify and clone novel sodium channel α-subunits. As described here, this work has led to the isolation and functional expression of PN3, a novel voltage-gated, TTX-resistant sodium channel expressed predominantly by small sensory neurons within the peripheral nervous system. tetrodotoxin dorsal root ganglion polymerase chain reaction reverse transcription sodium channel β1-subunit human rat. EcoRI-adapted cDNA was prepared from normal adult male Sprague-Dawley rat DRG poly(A)+ RNA using the SuperScript Choice System (Life Technologies, Inc.). cDNA (>4 kilobases) was selected by sucrose gradient fractionation (11.Kieffer B.L. Gene (Amst.). 1991; 109: 115-119Crossref PubMed Scopus (7) Google Scholar) ligated into the Zap Express vector (Stratagene) and packaged with the Gigapack II XL lambda packaging extract (Stratagene). Phage (3.5 × 105) were screened by filter hybridization with a 32P-labeled probe (bases 4637-5868 of rBIIa)(12.Auld V.J. Goldin A.L. Krafte D.S. Marshall J. Dunn J.M. Catterall W.A. Lester H.A. Davidson N. Dunn R.J. Neuron. 1988; 1: 449-461Abstract Full Text PDF PubMed Scopus (298) Google Scholar). Filters were hybridized in 50% formamide, 5 × saline/sodium/phosphate/EDTA, 5 × Denhardt's solution, 0.5% SDS, 250 μg/ml salmon sperm DNA, and 50 mM sodium phosphate at 42°C and washed in 0.5 × SSC, 0.1% SDS at 50°C. Positive clones were excised in vivo into pBK-CMV using the ExAssist/XLOLR system (Stratagene). Southern blots of EcoRI-digested plasmids were hybridized with a 32P-labeled DNA probe representing a novel domain IV segment amplified from DRG RNA by PCR with degenerate oligonucleotide primers. Southern filters were hybridized in 50% formamide, 6 × SSC, 5 × Denhardt's solution, 0.5% SDS, and 100 μg/ml salmon sperm DNA at 42°C and were washed in 0.1 × SSC, 0.1% SDS at 65°C. A cDNA clone, 7.3, containing a full-length insert, was identified and sequenced on both strands. In addition, several other PN3 clones were partially sequenced. Sequence analyses were done using the Gap, BestFit, PileUp, and Distances programs of the Wisconsin Sequence Analysis Package (Genetics Computer Group, Inc.). For oocyte expression analysis, the PN3 cDNA was excised from the vector and, after blunting the ends, subcloned into pBSTA. Tissues were isolated from anesthetized, normal adult male Sprague-Dawley rats and were immediately frozen at −80°C. RNA was isolated from tissue samples using RNAzol (Tel-Test, Inc.). Random-primed cDNA was reverse-transcribed from 500 ng of RNA from each tissue. PCR primers targeted the 3′-untranslated region of PN3 and defined a 410-base pair amplicon. Thermal cycler parameters were: 30 s/94°C, 30 s/57°C, 1 min/72°C (24 cycles); 30 s/94°C, 30 s/57°C, 5 min/72°C (1 cycle). A positive control (1 ng of pBK-CMV/PN3) and a no-template control were also included. cDNA from each tissue was also PCR amplified using primers specific for glyceraldehyde-3-phosphate dehydrogenase (13.Tso J.Y. Sun X.-H. Kao T.-H. Reece K.S. Wu R. Nucleic Acids Res. 1985; 13: 2485-2502Crossref PubMed Scopus (1757) Google Scholar) to demonstrate template viability. PN3 PCR amplicons from nodose ganglia and sciatic nerve were confirmed by nucleotide sequence analysis. Oligonucleotide probe sequences were synthesized from the unique 3′-untranslated region of PN3 (sense and antisense probes were complementary to each other). Normal rats were perfused with 4% paraformaldehyde; L4-L5 DRG were removed, postfixed in the same solution, and cryoprotected in 20% sucrose. Frozen sections (10 μm) were cut and hybridized overnight at 39°C in a solution containing 35S-ATP-labeled oligonucleotides (specific activity, 5 × 107-1 × 108 cpm/μg), 50% formamide, 4 × SSC, 0.5 mg/ml salmon sperm DNA, and 1 × Denhardt's solution. Sections were washed over a period of 6 h in 2 ×-0.1 × SSC containing 0.1%β-mercaptoethanol, dehydrated in a series of ethanols (50-100%) containing 0.3 M ammonium acetate, and apposed to sheet film (Amersham Bmax) or dipped in liquid emulsion (Amersham LM-1) and then developed for 2 and 5 weeks, respectively. The cell area of neurons (hybridized and non-hybridized) with a distinct nucleolus was measured from sections through the lumbar ganglia with the aid of a Macintosh Quadra 840 using the public domain NIH Image Program (W. Rasband, NIH). Capped cRNA was prepared from the linearized plasmid using a T7 in vitro transcription kit (Ambion, mMessage mMachine) and injected into stage V and VI Xenopus oocytes (14.Goldin A.L. Methods Enzymol. 1992; 207: 266-279Crossref PubMed Scopus (235) Google Scholar) using a Nanojector (Drummond). After 2.5 days at 20°C, oocytes were impaled with agarose-cushion electrodes (0.3-0.8 megaohm) (15.Schreibmayer W. Lester H.A. Dascal N. Pflügers Arch. 1994; 426: 453-458Crossref PubMed Scopus (147) Google Scholar) and voltage-clamped with a Geneclamp 500 amplifier (Axon Instruments) in TEV (two-electrode voltage clamp) mode. Stimulation and recording were controlled by a computer running pClamp (Axon Instruments). Oocytes were perfused with a solution containing (in mM): 81 NaCl, 2 KCl, 1 MgCl2, 0.3 CaCl2, 20 Hepes-NaOH (pH 7.5). The data in Fig. 5A were collected using the Geneclamp hardware leak subtraction, filtered at 5 kHz with a 4-pole Bessel filter, and sampled at 50 kHz. For the experiment in Fig. 5C, the oocytes were depolarized from −100 mV to +20 mV for approximately 10 ms at 0.1 Hz; P/-4 leak subtraction was used(16.Bezanilla F. Armstrong C.M. J. Gen. Physiol. 1977; 70: 549-566Crossref PubMed Scopus (644) Google Scholar). There was a slow “rundown” of the current with time, and a correction was made for the resulting sloping baseline. Varying concentrations of TTX (Sigma) in bath solution were perfused over the oocyte, and the current amplitude was allowed to attain steady state before the effect was recorded. To identify novel sodium channel α-subunits from the peripheral nervous system, we used degenerate oligonucleotide-primed RT-PCR analysis of RNA from rat DRG and homology cloning from a rat DRG cDNA library. PCR fragments from domain I and interdomain I-II were cloned and sequenced. The sequences matched those of clones 7.3 and 17.2 that were isolated from the rat DRG cDNA library by homology cloning. Clone 7.3 (PN3, peripheral nerve sodium channel 3) was sequenced entirely. Several other full-length and partial clones for PN3 were isolated. Nucleotide sequence analysis of the PN3 cDNA identified a 5868-base open reading frame, coding for a 1956-amino acid protein. In common with other sodium channels, there is an ATG 5 base pairs upstream of the genuine ATG. The deduced amino acid sequence of PN3 (Fig. 1) exhibited the primary structural features of an α-subunit of a voltage-gated sodium channel. PN3 contains four homologous domains (I-IV), each consisting of six putative α-helical transmembrane segments (S1-S6). The positively charged residues in the voltage sensor (S4 segments) and the inactivation gate between IIIS6 and IVS1 are highly conserved in PN3; sites for cAMP-dependent phosphorylation and N-linked glycosylation shown to exist in other sodium channels (1.Catterall W.A. Physiol. Rev. 1992; 72: S15-S48Crossref PubMed Google Scholar) are also present in PN3. In PN3, however, there are two unique consensus sites for cAMP-dependent phosphorylation sites, one in domain II between S3 and S4 and another in the interdomain II-III (Fig. 1). Modulation of rBIIa channel function by cAMP-dependent protein kinase A has been demonstrated(1.Catterall W.A. Physiol. Rev. 1992; 72: S15-S48Crossref PubMed Google Scholar, 17.Li M. West J.W. Numann R. Murphy B.J. Scheuer T. Catterall W.A. Science. 1993; 261: 1439-1442Crossref PubMed Scopus (231) Google Scholar, 18.Murphy B.J. Rossie S. De Jongh K.S. Catterall W.A. J. Biol. Chem. 1993; 268: 27355-27362Abstract Full Text PDF PubMed Google Scholar). The significance of the unique cAMP-dependent protein kinase A consensus sites in PN3 in vitro and in vivo remains to be demonstrated. In addition, there is an insertion of an additional Gln between Pro583 and Ala584 in several partial clones. The significance of the glutamine insertion has not been determined. Fig. 2A shows an amino acid homology comparison of PN3 with other cloned rat sodium channels. The higher sequence homology between PN3 and the TTX-insensitive cardiac channel and their slow inactivation kinetics (discussed below) suggest that they belong to a unique subfamily of sodium channels. Indeed, the Distance paradigm of the GCG program classifies PN3 and the cardiac sodium channel as a subfamily of sodium channels (Fig. 2A). In addition to PN3, partial clones for the following known sodium channels were isolated: rBI, rBIII, glial channel(19.Gautron S. Dos Santos G. Pinto-Henrique D. Koulakoff A. Gros F. Berwald-Netter Y. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 7272-7276Crossref PubMed Scopus (169) Google Scholar), and a rat ortholog of the human and mouse atypical sodium channels(20.George Jr., A.L. Knittle T.J. Tamkun M.M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 4893-4897Crossref PubMed Scopus (127) Google Scholar, 21.Felipe A. Knittle T.J. Doyle K.L. Tamkun M.M. J. Biol. Chem. 1994; 269: 30125-30131Abstract Full Text PDF PubMed Google Scholar). A β1-subunit was also cloned from the rat DRG by PCR. The rat DRG β1-subunit and rat brain sodium channel β1-subunit (rSCNβ1) have identical amino acid sequences. Human sodium channel β1-subunit (hSCNβ1) and rSCNβ1 (22.Isom L.L. De Jongh K.S. Patton D.E. Reber B.F. Offord J. Charbonneau H. Walsh K. Goldin A.L. Catterall W.A. Science. 1992; 256: 839-842Crossref PubMed Scopus (598) Google Scholar) are 96% identical. Northern blot analysis using the RT-PCR fragments and the 3′-untranslated region of clone 7.3 as probes showed that PN3 is encoded by a 7.5-kilobase transcript (data not shown). This band was absent in both brain and spinal cord. Analysis of RNA from selected rat tissues by RT-PCR (Fig. 2B) suggests that PN3 mRNA expression was limited to DRG, nodose ganglia, and to a lesser extent, sciatic nerve of the peripheral nervous system (35 cycles of PCR). No signal was present in the sciatic nerve after 25 cycles of amplification. PN3 mRNA was not detected in brain, spinal cord, superior cervical ganglia, heart, or skeletal muscle after 35 cycles of amplification. Additional RT-PCR analyses of DRG mRNA have detected other sodium channels including rBI(23.Noda M. Ikeda T. Kayano T. Suzuki H. Takeshima H. Kurasaki M. Takahashi H. Numa S. Nature. 1986; 320: 188-192Crossref PubMed Scopus (685) Google Scholar), rBIII(24.Kayano T. Noda M. Flockerzi V. Takahashi H. Numa S. FEBS Lett. 1988; 228: 187-194Crossref PubMed Scopus (265) Google Scholar), rH1(25.Rogart R.B. Cribbs L.L. Muglia L.K. Kephart D. Kaiser M.W. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 8170-8174Crossref PubMed Scopus (307) Google Scholar), peripheral nerve sodium channel type 1 (PN1)(26.D'Arcangelo G. Paradiso K. Shepard D. Brehm P. Halegoua S. Mandel G. J. Cell Biol. 1993; 122: 915-921Crossref PubMed Scopus (108) Google Scholar), SCP6(27.Schaller K.L. Krzemien D.M. Yarowsky P.J. Krueger B.K. Caldwell J.H. J. Neurosci. 1995; 15: 3231-3242Crossref PubMed Google Scholar), and other novel sodium channel α-subunits (data not shown). In situ hybridization using PN3-specific oligonucleotide probes showed that PN3 mRNA was expressed predominantly by small neurons in rat DRG (Fig. 3). Approximately 76% of the small cell population (400-1000 μm2) and 33% of the large cell population (1400-2000 μm2) were hybridized with probes for PN3 (Fig. 4). Recently, Akopian and Wood (28.Akopian A.N. Wood J.N. J. Biol. Chem. 1995; 270: 21264-21270Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar) isolated a partial cDNA clone, G7, from a rat DRG cDNA library with homology to known sodium channels and specific expression in subsets of sensory neurons. Whether PN3 and G7 are the same gene is unknown at present.Figure 4:Frequency distribution histogram of somal areas from sections through lumbar DRG. The number of neurons hybridized with PN3 is shown by filled bars (n = 246). The number of non-hybridized neurons is shown by hatched bars (n = 215).View Large Image Figure ViewerDownload (PPT) Two electrode voltage clamp recordings from Xenopus oocytes injected with PN3 cRNA indicated that expression of PN3 produced an inward current with slow inactivation kinetics (Fig. 5A). This current was voltage-dependent (Fig. 5B) and is carried by sodium ions; reduction of extracellular sodium ion concentration (by substituting N-methyl-D-glucamine) from 91 to 50 and 21 mM resulted in hyperpolarizing shifts in the reversal potential from +43 mV to +12 mV and −22 mV, respectively. Examination of the current-voltage relationship for PN3 (Fig. 5B) reveals a strikingly depolarized activation potential. In this expression system, PN3 exhibits little or no activation at −10 mV, whereas most cloned sodium channels begin to activate between −60 and −30 mV(29.Cribbs L. Satin J. Fozzard H.A. Rogart R.B. FEBS Lett. 1990; 275: 195-200Crossref PubMed Scopus (52) Google Scholar, 30.Patton D.E. Goldin A.L. Neuron. 1991; 7: 637-647Abstract Full Text PDF PubMed Scopus (63) Google Scholar, 31.Trimmer J.S. Cooperman S.S. Tomiko S.A. Zhou J.Y. Crean S.M. Boyle M.B. Kallen R.G. Sheng Z.H. Barchi R.L. Sigworth F.J. Goodman R.H. Agnew W.S. Mandel G. Neuron. 1989; 3: 33-49Abstract Full Text PDF PubMed Scopus (484) Google Scholar). The currents produced by injection of PN3 cRNA had slow inactivation kinetics (Fig. 5A). rBIIa, rBIII, and rSkM1 sodium channels also produce currents with slow inactivation kinetics when injected into Xenopus oocytes; coexpression of the β1-subunit greatly accelerates the inactivation kinetics of these channels(22.Isom L.L. De Jongh K.S. Patton D.E. Reber B.F. Offord J. Charbonneau H. Walsh K. Goldin A.L. Catterall W.A. Science. 1992; 256: 839-842Crossref PubMed Scopus (598) Google Scholar, 32.Cannon S.C. McClatchey A.I. Gusella J.F. Pflügers Arch. 1993; 423: 155-157Crossref PubMed Scopus (79) Google Scholar, 33.Wallner M. Weigel L. Meera P. Lotan I. FEBS Lett. 1993; 336: 535-539Crossref PubMed Scopus (49) Google Scholar, 34.Yang J.S. Bennet P.B. Makita N. George A.L. Barchi R.L. Neuron. 1993; 11: 915-922Abstract Full Text PDF PubMed Scopus (60) Google Scholar, 35.Patton D.E. Isom L.L. Catterall W.A. Goldin A.L. J. Biol. Chem. 1994; 269: 17649-17655Abstract Full Text PDF PubMed Google Scholar). However, coinjection of 1.3 ng of human sodium channel β1-subunit (hSCNβ1) (36.McClatchey A.L. Cannon S.C. Slaugenhaupt S.A. Gusella J.F. Hum. Mol. Genet. 1993; 2: 745-749Crossref PubMed Scopus (70) Google Scholar) cRNA, which is homologous to the rat brain and DRG SCNβ1, with PN3 cRNA did not accelerate the inactivation kinetics (data not shown). In contrast, coexpression of this quantity of hSCNβ1 cRNA with rSkM1 cRNA was sufficient to accelerate the inactivation kinetics of rSkM1 maximally. Therefore, PN3 may possess inherently slow kinetics. When expressed in Xenopus oocytes, the PN3 sodium current is highly resistant to TTX (IC50≥ 100 μM) (Fig. 5C). The TTX-sensitive brain and skeletal muscle sodium channels are blocked by nanomolar TTX concentrations, whereas the TTX-insensitive cardiac sodium channels are blocked by micromolar TTX concentrations(2.White J.A. Alonso A. Kay A.R. Neuron. 1993; 11: 1037-1047Abstract Full Text PDF PubMed Scopus (69) Google Scholar). In rat heart sodium channel 1 (rH1), Cys374 is a critical determinant of TTX insensitivity (37.Backx P.H. Yue D.T. Lawrence J.H. Marban E. Tomaselli G.F. Science. 1992; 257: 248-251Crossref PubMed Scopus (240) Google Scholar, 38.Chen L.-Q. Chahine M. Kallen R.G. Barch R.L. Horn R. FEBS Lett. 1992; 309: 253-257Crossref PubMed Scopus (77) Google Scholar, 39.Satin J. Kyle J.W. Chen M. Bell P. Cribbs L.L. Fozzard H.A. Rogart R.B. Science. 1992; 256: 1202-1205Crossref PubMed Scopus (332) Google Scholar); in the TTX-sensitive rBI, rBII, rBIII, and rSkM1, the corresponding residue is an aromatic amino acid, either Phe or Tyr, the aromatic ring of which facilitates the binding of TTX to the protein. In PN3, this position is occupied by a Ser residue (Ser356), which may explain the unique response to TTX. Site-directed mutagenesis of this residue to Phe/Tyr or Cys will determine whether this amino acid residue is solely responsible for TTX resistance. TTX-resistant sodium currents have been implicated in peripheral and central neuronal sensitization mediated by the C-fibers of small neurons following peripheral tissue damage and nerve injury. The biophysical and pharmacological properties of PN3 suggest that it contributes to the TTX-resistant sodium currents in small neurons of DRG. PN3 may, therefore, play a role in the the sensory function and dysfunction that is characteristic of pathophysiological pain processing. In addition, we suggest that PN3 may conduct TTX-resistant sodium currents in other sensory ganglia of the peripheral nervous system such as nodose ganglia(40.Ikeda S.R. Schofield G.G. Weight F.F. J. Neurophysiol. 1986; 55: 527-539Crossref PubMed Scopus (112) Google Scholar). We thank C. Yee, P. Zuppan, and C. Bach for sequence analysis and oligonucleotide synthesis. L. Hedley and G. Faurot assisted in DRG isolations. A. L. Goldin and G. Mandel kindly provided plasmid pBSTA and SkM1 plasmid DNA, respectively. We also thank H. Chan, D. Clarke, and R. Whiting for their interest and encouragement during the course of this work." @default.
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• W2000702493 title "Structure and Function of a Novel Voltage-gated, Tetrodotoxin-resistant Sodium Channel Specific to Sensory Neurons" @default.
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