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71.
Sodium balance determines the extracellular fluid volume and sets arterial blood pressure (BP). Chronically raised BP (hypertension)
represents a major health risk in Western societies. The relationship between BP and renal sodium excretion (the pressure/natriuresis
relationship) represents the key element in defining the BP homeostatic set point. The renin–angiotensin–aldosterone system
(RAAS) makes major adjustments to the rates of renal sodium secretion, but this system works slowly over a period of hours
to days. More rapid adjustments can be made by the sympathetic nervous system, although the kidney can function well without
sympathetic nerves. Attention has now focussed on regulatory mechanisms within the kidney, including extracellular nucleotides
and the P2 receptor system. Here, we discuss how extracellular ATP can control renal sodium excretion by altering the activity
of epithelial sodium channels (ENaC) present in the apical membrane of principal cells. There remains considerable controversy
over the molecular targets for released ATP, although the P2Y2 receptor has received much attention. We review the available data and reflect on our own findings in which ATP-activated
P2Y and P2X receptors make adjustments to ENaC activity and therefore sodium excretion. 相似文献
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Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype. 总被引:1,自引:0,他引:1
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H Allayee B E Aouizerat R M Cantor G M Dallinga-Thie R M Krauss C D Lanning J I Rotter A J Lusis T W de Bruin 《American journal of human genetics》1998,63(2):577-585
Small, dense LDL particles consistently have been associated with hypertriglyceridemia, premature coronary artery disease (CAD), and familial combined hyperlipidemia (FCH). Previously, we have observed linkage of LDL particle size with four separate candidate-gene loci in a study of families enriched for CAD. These loci contain the genes for manganese superoxide dismutase (MnSOD), on chromosome 6q; for apolipoprotein AI-CIII-AIV, on chromosome 11q; for cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), on chromosome 16q; and for the LDL receptor (LDLR), on chromosome 19p. We have now tested whether these loci also contribute to LDL particle size in families ascertained for FCH. The members of 18 families (481 individuals) were typed for genetic markers at the four loci, and linkage to LDL particle size was assessed by nonparametric sib-pair linkage analysis. The presence of small, dense LDL (pattern B) was much more frequent in the FCH probands (39%) than in the spouse controls (4%). Evidence for linkage was observed at the MnSOD (P=.02), CETP/LCAT (P=.03), and apolipoprotein AI-CIII-AIV loci (P=.005) but not at the LDLR locus. We conclude that there is a genetically based association between FCH and small, dense LDL and that the genetic determinants for LDL particle size are shared, at least in part, among FCH families and the more general population at risk for CAD. 相似文献
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77.
We recently reported that bile salts play a role in the regulation of mucin
secretion by cultured dog gallbladder epithelial cells. In this study we
have examined whether bile salts also influence mucin secretion by the
human epithelial colon cell line LS174T. Solutions of bile salts were
applied to monolayers of LS174T cells. Mucin secretion was quantified by
measuring the secretion of [3H]GlcNAc labeled glycoproteins. Both
unconjugated bile salts as well as taurine conjugated bile salts stimulated
mucin secretion by the colon cells in a dose-dependent fashion. Hydrophobic
bile salts were more potent stimulators than hydrophilic bile salts. Free
(unconjugated) bile salts were more stimulatory compared with their taurine
conjugated counterparts. Stimulation of mucin secretion by LS174T cells was
found to occur at much lower bile salt concentrations than in the
experiments with the dog gallbladder epithelial cells. The protein kinase C
activators PMA and PDB had no stimulatory effect on mucin secretion. We
conclude that mucin secretion by the human colon epithelial cell line
LS174T is regulated by bile salts. We suggest that regulation of mucin
secretion by bile salts might be a common mechanism, by which different
epithelia protect themselves against the detergent action of bile salts, to
which they are exposed throughout the gastrointestinal tract.
相似文献
78.
The armadillo protein SmgGDS promotes guanine nucleotide exchange by small GTPases containing a C-terminal polybasic region (PBR), such as Rac1 and RhoA. Because the PBR resembles a nuclear localization signal (NLS) sequence, we investigated the nuclear transport of SmgGDS with Rac1 or RhoA. We show that the Rac1 PBR has significant NLS activity when it is fused to green fluorescent protein (GFP) or in the context of full-length Rac1. In contrast, the RhoA PBR has very poor NLS activity when it is fused to GFP or in the context of full-length RhoA. The nuclear accumulation of both Rac1 and SmgGDS is enhanced by Rac1 activation and diminished by mutation of the Rac1 PBR. Conversely, SmgGDS nuclear accumulation is diminished by interactions with RhoA. An SmgGDS nuclear export signal sequence that we identified promotes SmgGDS nuclear export. These results suggest that SmgGDS. Rac1 complexes accumulate in the nucleus because the Rac1 PBR has NLS activity and because Rac1 supplies the appropriate GTP-dependent signal. In contrast, SmgGDS.RhoA complexes accumulate in the cytoplasm because the RhoA PBR does not have NLS activity. This model may be applicable to other armadillo proteins in addition to SmgGDS, because we demonstrate that activated Rac1 and RhoA also provide stimulatory and inhibitory signals, respectively, for the nuclear accumulation of p120 catenin. These results indicate that small GTPases with a PBR can regulate the nuclear transport of armadillo proteins. 相似文献
79.
Oliver Beckstein Ekaterina Ivanova Tian Geng Simone Weyand David Drew Joseph Lanigan David J Sharples Mark SP Sansom So Iwata Colin WG Fishwick A Peter Johnson Alexander D Cameron Peter JF Henderson 《The EMBO journal》2014,33(16):1831-1844
The hydantoin transporter Mhp1 is a sodium‐coupled secondary active transport protein of the nucleobase‐cation‐symport family and a member of the widespread 5‐helix inverted repeat superfamily of transporters. The structure of Mhp1 was previously solved in three different conformations providing insight into the molecular basis of the alternating access mechanism. Here, we elucidate detailed events of substrate binding, through a combination of crystallography, molecular dynamics, site‐directed mutagenesis, biochemical/biophysical assays, and the design and synthesis of novel ligands. We show precisely where 5‐substituted hydantoin substrates bind in an extended configuration at the interface of the bundle and hash domains. They are recognised through hydrogen bonds to the hydantoin moiety and the complementarity of the 5‐substituent for a hydrophobic pocket in the protein. Furthermore, we describe a novel structure of an intermediate state of the protein with the external thin gate locked open by an inhibitor, 5‐(2‐naphthylmethyl)‐L‐hydantoin, which becomes a substrate when leucine 363 is changed to an alanine. We deduce the molecular events that underlie acquisition and transport of a ligand by Mhp1. 相似文献
80.
Li Sheng-Fowler Wei Tu Haiqing Fu Haruhiko Murata Lynda Lanning Gideon Foseh Juliete Macauley Donald Blair Stephen H. Hughes John M. Coffin Andrew M. Lewis Jr Keith Peden 《PloS one》2014,9(10)
As part of safety studies to evaluate the risk of residual cellular DNA in vaccines manufactured in tumorigenic cells, we have been developing in vivo assays to detect and quantify the oncogenic activity of DNA. We generated a plasmid expressing both an activated human H-ras gene and murine c-myc gene and showed that 1 µg of this plasmid, pMSV-T24-H-ras/MSV-c-myc, was capable of inducing tumors in newborn NIH Swiss mice. However, to be able to detect the oncogenicity of dominant activated oncogenes in cellular DNA, a more sensitive system was needed. In this paper, we demonstrate that the newborn CD3 epsilon transgenic mouse, which is defective in both T-cell and NK-cell functions, can detect the oncogenic activity of 25 ng of the circular form of pMSV-T24-H-ras/MSV-c-myc. When this plasmid was inoculated as linear DNA, amounts of DNA as low as 800 pg were capable of inducing tumors. Animals were found that had multiple tumors, and these tumors were independent and likely clonal. These results demonstrate that the newborn CD3 epsilon mouse is highly sensitive for the detection of oncogenic activity of DNA. To determine whether it can detect the oncogenic activity of cellular DNA derived from four human tumor-cell lines (HeLa, A549, HT-1080, and CEM), DNA (100 µg) was inoculated into newborn CD3 epsilon mice both in the presence of 1 µg of linear pMSV-T24-H-ras/MSV-c-myc as positive control and in its absence. While tumors were induced in 100% of mice with the positive-control plasmid, no tumors were induced in mice receiving any of the tumor DNAs alone. These results demonstrate that detection of oncogenes in cellular DNA derived from four human tumor-derived cell lines in this mouse system was not possible; the results also show the importance of including a positive-control plasmid to detect inhibitory effects of the cellular DNA. 相似文献