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81.
Franco R Rodríguez R Pasantes-Morales H 《Pflügers Archiv : European journal of physiology》2004,449(2):159-169
Reducing osmolarity by 35% increased 3H-taurine efflux from Swiss 3T3 fibroblasts from 0.5% to a peak of 5.7%. The presence of ATP (10–100 µM; EC50 1.5 µM) increased taurine efflux up to 10%, and decreased the set point for hyposmotically stimulated taurine release (HTR). ATP potentiation was mimicked by UTP, reduced by addition of suramin and pyridoxal phosphate-6-azophenyl-2,4-disulphonic acid (PPADS) and unaffected by ADP, ,-methylene-ATP (,-ATP) or 2-methylthio-ATP (Me-ATP), suggesting its mediation by purinergic P2Y2 and P2Y4 metabotropic receptors. Under isosmotic conditions ATP increased the cytosolic [Ca2+] ([Ca2+]i) markedly, but did not increase taurine release. HTR was independent of external Ca2+ but was reduced (by 56–59%) by BAPTA-AM, thapsigargin-induced depletion of intracellular Ca2+ stores, or phospholipase C (PLC) inhibition. Blockade of calmodulin (CaM) or calmodulin kinase II (CaMKII) reduced HTR by 54% and 76%, respectively. The ATP-mediated potentiation was prevented fully by all these treatments. HTR was reduced by 30–50% by blockers of protein tyrosine kinases (AG18), phosphoinositide 3-kinase (PI3K) (wortmannin), p21rho (toxin B), p21rho-kinase (Y27632) and the stress-activated kinase p38 (PD169316). ATP-mediated potentiation was reduced similarly by these blockers. Simultaneous inhibition of PI3K and CaMKII abolished HTR. Altogether, these results suggest a modulatory effect of ATP, probably exerted by a potentiation of the Ca2+-dependent fraction of HTR. This fraction has as signalling elements a PLC-dependent [Ca2+]i increase, resulting from Ca2+ released from thapsigargin-sensitive internal stores, followed by activation of CaM/CaMKII reactions. The Ca2+/ATP effect operates only when the Ca2+-independent, tyrosine kinase-mediated pathway is already activated. Suggested elements of cross-talk between the two pathways are PLC, PI3K and CaMKII. 相似文献
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84.
Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus 总被引:13,自引:0,他引:13
Asumalahti K Veal C Laitinen T Suomela S Allen M Elomaa O Moser M de Cid R Ripatti S Vorechovsky I Marcusson JA Nakagawa H Lazaro C Estivill X Capon F Novelli G Saarialho-Kere U Barker J Trembath R Kere J;Psoriasis Consortium 《Human molecular genetics》2002,11(5):589-597
PSORS1, near HLA-C, is the major genetic determinant of psoriasis. We present genetic and structural evidence suggesting a major role for the HCR gene at the PSORS1 locus. Genotyping of 419 families from six populations revealed that coding single-nucleotide polymorphisms of HCR formed a conserved allele HCR*WWCC that associated highly significantly with psoriasis and with the HLA-Cw6 allele in all populations. Because of strong linkage disequilibrium between HLA-Cw6 and HCR*WWCC, the two genes could not be genetically distinguished by this sample size. However, the variant HCR allele was predicted to differ in secondary structure from the wild-type protein. HCR protein expression in lesional psoriatic skin differed considerably from that observed in normal skin. These results provide strong evidence for the HCR*WWCC allele as a major genetic determinant for psoriasis, probably by a mechanism impacting on keratinocyte proliferation. 相似文献
85.
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The cholesteryl ester transfer protein (CETP) locus as a candidate gene in abdominal aortic aneurysm
Dorothy Ramsbottom Anne O'Neill Donna M. Sexton Rafael A. Gafoor David Bouchier-Hayes David T. Croke 《Clinical genetics》1997,51(4):241-245
Abdominal aortic aneurysm (AAA) is a relatively common disease of the elderly presenting as progressive dilatation of the abdominal aorta. The condition shows a pronounced tendency to cluster in families, indicating a genetic component in the disease aetiology. We have screened the cholesteryl ester transfer protein (CETP) gene, which has been proposed as a candidate gene in AAA, by means of SSCP, DNA sequencing and restriction analysis in a cohort of patients with AAA and a matching control group drawn from the Irish population. The analysis has demonstrated sequence variation at four sites in the CETP gene: an A-T transversion in exon 9 (producing a Lys309-Stop codon substitution), a G-A transition in exon 14 (producing a conservative Va1421-Ile substitution), a C-T transition in intron 12 and a G-A transition in intron 15. None of the last three sites corresponded with sites of functional significance in the protein, suggesting that this reflects neutral polymorphism at the CETP locus. Furthermore, the frequencies of these four polymorphisms in the AAA patient and control groups were not significantly different. These data therefore suggest that CETP may be excluded as a candidate gene in abdominal aortic aneurysm. 相似文献
88.
Baldomero Lara Luis Gandía Rafael Martínez-Sierra Andrés Torres A. G. García 《Pflügers Archiv : European journal of physiology》1998,435(4):472-478
This study uses a new strategy to investigate the hypothesis that, of the various Ca2+ channels expressed by a neurosecretory cell, a given channel subtype is coupled more tightly to the exocytotic apparatus
than others. The approach is based on the prediction that the degree of inhibition of the secretory response by various Ca2+ channel blockers will differ at low (0.5 mM) and high (5 mM) extracellular Ca2+ concentrations ([Ca2+]o). So, at low [Ca2+]o the K+-evoked catecholamine release from superfused bovine chromaffin cells was depressed 60–70% by 2 μM ω-agatoxin IVA (P/Q-type
Ca2+ channel blockade), by 3 μM ω-conotoxin MVIIC (N/P/Q-type Ca2+ channel blockade), or by 3 μM lubeluzole (N/P/Q-type Ca2+ channel blockade); in high [Ca2+]o these blockers inhibited the responses by only 20–35%. At 1–3 μM ω-conotoxin GVIA (N-type Ca2+ channel blockade) or 3 μM furnidipine (L-type Ca2+ channel blockade), secretion was inhibited by 30 and 50%, respectively; such inhibitory effects were similar in low or high
[Ca2+]o. Combined furnidipine plus ω-conotoxin MVIIC, ω-agatoxin IVA or ω-conotoxin GVIA exhibited additive blocking effects at
both Ca2+ concentrations. The results suggest that Q-type Ca2+ channels are coupled more tightly to exocytotic active sites, as compared to L-type channels. This hypothesis if founded
in the fact that external Ca2+ that enters the cell through a Ca2+ channel located near to chromaffin vesicles will saturate the K+ secretory response at both [Ca2+]o, i.e. 0.5 mM and 5 mM. In contrast, Ca2+ ions entering through more distant channels will be sequestered by intracellular buffers and, thus, will not saturate the
secretory machinery at lower [Ca2+]o.
Received: 23 September 1997 / Received after revision: 29 October 1997 / Accepted: 30 October 1997 相似文献
89.
90.
Laboratory detection of Haemophilus influenzae with decreased susceptibility to nalidixic acid, ciprofloxacin, levofloxacin, and moxifloxacin due to GyrA and ParC mutations 下载免费PDF全文
Pérez-Vázquez M Román F Aracil B Cantón R Campos J 《Journal of clinical microbiology》2004,42(3):1185-1191
The detection of clinical isolates with decreased fluoroquinolone susceptibilities and a resistance mechanism is of epidemiological and clinical interest. We studied the susceptibilities of 62 clinical isolates and 2 American Type Culture Collection reference strains of Haemophilus influenzae to ciprofloxacin, levofloxacin, moxifloxacin, and nalidixic acid by the microdilution and disk diffusion methods. The ciprofloxacin MICs for 34 of the isolates were >/=0.12 micro g/ml (range, 0.12 to 32 micro g/ml), and the ciprofloxacin MICs for 28 matched control isolates were =0.06 micro g/ml. In addition, we sequenced the quinolone resistance-determining regions (QRDRs) of gyrA and parC of all strains. The log(2) MICs of all quinolones were plotted against the inhibition zone diameters. The MICs and inhibition zone diameters selected to screen for the resistance mechanism were based on the susceptibility distribution data and the presence or absence of amino acid changes in the QRDRs of GyrA and ParC. Strains for which ciprofloxacin MICs were =0.06 micro g/ml, levofloxacin and moxifloxacin MICs were =0.03 micro g/ml, and nalidixic acid MICs were =2.0 micro g/ml lacked modifications in the QRDR of GyrA. In contrast, all strains for which ciprofloxacin, levofloxacin, and moxifloxacin MICs were >/=0.5 micro g/ml and the vast majority of those for which nalidixic acid MICs were >/=32 micro g/ml exhibited amino acid changes in GyrA and ParC. Nalidixic acid and the other three fluoroquinolones studied could be used to screen H. influenzae isolates for the detection of decreased susceptibilities to quinolones due to the acquisition of two amino acid changes in the QRDRs of GyrA and ParC (sensitivity, >95%; specificity, >80%). 相似文献