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SN Elkind 《Canadian Metallurgical Quarterly》1994,54(1):3-13; discussion 15-9
25.
SN Schiffmann F Desdouits R Menu P Greengard JD Vincent JJ Vanderhaeghen JA Girault 《Canadian Metallurgical Quarterly》1998,10(4):1312-1320
DARPP-32 is a cyclic adenosine monophosphate-regulated inhibitor of protein phosphatase 1, highly enriched in striatonigral neurons. Stimulation of dopamine D1 receptors increases phosphorylation of DARPP-32, whereas glutamate acting on N-methyl-D-aspartate receptors induces its dephosphorylation. Yet, to date, there is little direct evidence for the function of DARPP-32 in striatal neurons. Using a whole cell patch-clamp technique, we have studied the role of DARPP-32 in the regulation of voltage-gated sodium channels in rat striatal neurons maintained in primary culture. Injection of phospho-DARPP-32, but not of the unphosphorylated form, reduced the sodium current amplitude. This effect was similar to those induced by okadaic acid, with which there was no additivity and by tautomycin. Our results indicate that, in striatal neurons, sodium channels are under dynamic control by phosphorylation/dephosphorylation, and that phospho-DARPP-32 reduces sodium current by stabilizing a phosphorylated state of the channel or an associated regulatory protein. We propose that the DARPP-32-mediated modulation of sodium channels, via inhibition of phosphatase 1, contributes to the regulation of these channels by D1 receptors and other neurotransmitters which influence the state of phosphorylation of DARPP-32. 相似文献
26.
Mario Cano-Muoz Julie Lucas Li-Yun Lin Samuele Cesaro Christiane Moog Francisco Conejero-Lara 《International journal of molecular sciences》2022,23(5)
Inhibition of the HIV-1 fusion process constitutes a promising strategy to neutralize the virus at an early stage before it enters the cell. In this process, the envelope glycoprotein (Env) plays a central role by promoting membrane fusion. We previously identified a vulnerability at the flexible C-terminal end of the gp41 C-terminal heptad repeat (CHR) region to inhibition by a single-chain miniprotein (named covNHR-N) that mimics the first half of the gp41 N-terminal heptad repeat (NHR). The miniprotein exhibited low stability, moderate binding to its complementary CHR region, both as an isolated peptide and in native trimeric Envs, and low inhibitory activity against a panel of pseudoviruses. The addition of a disulfide bond stabilizing the miniprotein increased its inhibitory activity, without altering the binding affinity. Here, to further study the effect of conformational stability on binding and inhibitory potency, we additionally stabilized these miniproteins by engineering a second disulfide bond stapling their N-terminal end, The new disulfide-bond strongly stabilizes the protein, increases binding affinity for the CHR target and strongly improves inhibitory activity against several HIV-1 strains. Moreover, high inhibitory activity could be achieved without targeting the preserved hydrophobic pocket motif of gp41. These results may have implications in the discovery of new strategies to inhibit HIV targeting the gp41 CHR region. 相似文献
27.
L Ohno-Machado JH Gennari SN Murphy NL Jain SW Tu DE Oliver E Pattison-Gordon RA Greenes EH Shortliffe GO Barnett 《Canadian Metallurgical Quarterly》1998,5(4):357-372
Carboxylate and sulfate groups were introduced at the surface of poly(ethylene) (PE) samples. This was accomplished by coating and immobilizing sodium 10-undecenoate (C11(:)) and 10-undecene sulfate (S11(:)) on the polymer by means of an argon plasma treatment. The composition of the coated surfactant layer was proportional to the composition of the coating solution. The thickness of the surfactant layer on the surface of PE samples, which were precoated from an aqueous solution with a total surfactant concentration of 0.30 M, was about 55 A. The presence of carboxylate and sulfate groups after plasma treatment of the precoated surfaces was confirmed by X-ray photoelectron spectroscopy (XPS). About 20% of the initial amount of functional groups of the coated surfactants was retained at the PE surface. The ratio of carboxylate/sulfate groups at the plasma treated surfaces was dependent on the composition of the precoated surfaces. The minimum surface density of these groups on the resulting samples was about one group per 40 A2. 相似文献
28.
AE Medvedev T Flo RR Ingalls DT Golenbock G Teti SN Vogel T Espevik 《Canadian Metallurgical Quarterly》1998,160(9):4535-4542
This study was undertaken to evaluate the role of CD14 and complement receptors type 3 (CR3) and 4 (CR4) in mediating TNF release and NF-kappaB activation induced by LPS and cell wall preparations from group B streptococci type III (GBS). LPS and GBS caused TNF secretion from human monocytes in a CD14-dependent manner, and soluble CD14, LPS binding protein, or their combination potentiated both LPS- and GBS-induced activities. Blocking of either CD14 or CD18, the common beta-subunit of CR3 and CR4, decreased GBS-induced TNF release, while LPS-mediated TNF production was inhibited by anti-CD14 mAb only. Chinese hamster ovary cell transfectants (CHO) that express human CD14 (CHO/CD14) responded to both LPS and GBS with NF-kappaB translocation, which was inhibited by anti-CD14 mAb and enhanced by LPS binding protein. While LPS showed fast kinetics of NF-kappaB activation in CHO/CD14 cells, a slower NF-kappaB response was induced by GBS. LPS also activated NF-kappaB in CHO cells transfected with either human CR3 or CR4 cDNA, although responses were delayed and weaker than those of CHO/CD14 cells. In contrast to LPS, GBS failed to induce NF-kappaB in CHO/CR3 or CHO/CR4 cells. Both C3H/OuJ (Lps[n]) and C3H/HeJ (Lps[d]) mouse peritoneal macrophages responded to GBS with TNF production and NF-kappaB translocation, whereas LPS was active only in C3H/OuJ macrophages. Thus, LPS and GBS differentially involve CD14 and CR3 or CR4 for signaling NF-kappaB activation in CHO cells and TNF release in human monocytes, and engage a different set of receptors and/or intracellular signaling pathways in mouse macrophages. 相似文献
29.
JJ Gao MB Filla MJ Fultz SN Vogel SW Russell WJ Murphy 《Canadian Metallurgical Quarterly》1998,161(9):4803-4810
30.
IM Bell JM Erb RM Freidinger SN Gallicchio JP Guare MT Guidotti RA Halpin DW Hobbs CF Homnick MS Kuo EV Lis DJ Mathre SR Michelson JM Pawluczyk DJ Pettibone DR Reiss S Vickers PD Williams CJ Woyden 《Canadian Metallurgical Quarterly》1998,41(12):2146-2163
The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases. 相似文献