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41.
Summary The effects of several sulfamoyl benzoic acid derivatives on Na–K–Cl cotransport were investigated in winter flounder intestine. The relative efficacy (IC50 values) and order of potency of these derivatives were benzmetanide, 5×10–8
m> bumetanide 3×10–7
m>piretanide 3×10–6
m>furosemide 7×10–6
m> amino piretanide 1×10–5 3-amino-4-penoxy-5-sulfamoyl benzoic acid. Binding of [3H] bumetanide was studied in microsomal membranes from winter flounder intestine and compared to that in bovine kidney outer medulla. Binding was also studied in brush-border membranes from winter flounder intestine. The estimated values forK
d
and number of binding sites (n) were: bovine kidney,K
d
=1.6×10–7,n=10.5 pmol/mg protein; winter flounder intestine,K
d
1.2×10–7,n=7.3 pmol/mg protein, and brush-border membranes from winter flounder,K
d
=5.3×10–7,n=20.4 pmol/mg protein. The estimatedK
d
for bumetamide binding to winter flounder brush-border membranes derived from association and dissociation kinetics was 6.8×10–7
m. The similarity in magnitudes of IC50 andK
d
for bumetanide suggests that the brush-border cotransporter is ordinarily rate-limiting for transmural salt absorption and that bumetanide specifically binds to the cotransporter. Measurement of bumetanide binding at various concentrations of Na, K and Cl showed that optimal binding required all three ions to be present at about 5mm concentrations. Higher Na and K concentrations did not diminish binding but higher Cl concentrations (up to 100mm Cl) inhibited bumetanide binding by as much as 50%. Still higher Cl concentrations (500 and 900mm) did not further inhibit bumetanide binding. Scatchard analysis of bumetanide binding at 5 and 100mm Cl concentrations showed that bothK
d
andn were lower at the higher Cl concentration (5mm Cl:K
d
=5.29×10–7
m,n=20.4 pmol/mg protein; 100mm Cl:K
d
=2.3×10–7
m,n=8.8 pmol/mg protein). These data suggest two possibilities: that bumetanide and Cl binding are not mutually exclusive (in contrast to pure competitive inhibition) and that they each bind to separate sites or that two distinct bumetanide binding sites exist, only one of which exhibits Cl inhibition of binding. This inhibition would then be consistent with a competitive interaction with Cl. 相似文献
42.
Identification of the major Mr 100,000 substrate for calmodulin-dependent protein kinase III in mammalian cells as elongation factor-2 总被引:12,自引:0,他引:12
The major substrate for Ca2+/calmodulin-dependent protein kinase III in mammalian cells is a species of Mr 100,000 that has a primarily cytoplasmic localization. This substrate has now been identified as elongation factor-2 (EF-2), a protein that catalyzes the translocation of peptidyl-tRNA on the ribosome. The amino acid sequence of 18 residues from the N-terminal of the Mr 100,000 CaM-dependent protein kinase III substrate purified from rat pancreas was found to be identical to the N-terminal sequence of authentic rat EF-2 as previously deduced from nucleic acid sequencing of a cDNA (Kohno, K., Uchida, T., Ohkubo, H., Nakanishi, S., Nakanishi, T., Fukui, T., Ohtsuka, E., Ikehara, M., and Okada, Y. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 4978-4982). CaM-dependent protein kinase III phosphorylated EF-2 in vitro with a stoichiometry of approximately 1 mol/mol on a threonine residue. Amino acid sequencing of the purified tryptic phosphopeptide revealed that this threonine residue lies within the sequence: Ala-Gly-Glu-Thr-Arg-Phe-Thr-Asp-Thr-Arg (residues 51-60 of EF-2). The Mr 100,000 protein was stoichiometrically ADP-ribosylated in vitro by the addition of diphtheria toxin and NAD. The Mr 100,000 protein was photoaffinity labeled with a GTP analog and the protein had an endogenous GTPase activity that could be stimulated by the addition of salt-washed ribosomes. These properties are all characteristic of EF-2. Dephospho-EF-2 could support poly(U)-directed polyphenylalanine synthesis in a reconstituted elongation system when combined with EF-1. In the same system, phospho-EF-2 was virtually inactive in supporting polypeptide synthesis; this effect could be reversed by dephosphorylation of phospho-EF-2. These results suggest that intracellular Ca2+ inhibits protein synthesis in mammalian cells via CaM-dependent protein kinase III-catalyzed phosphorylation of EF-2. 相似文献
43.
H C Palfrey A C Nairn L L Muldoon M L Villereal 《The Journal of biological chemistry》1987,262(20):9785-9792
Growth-arrested human fibroblasts respond to mitogenic stimulation with a rapid, transient increase in cytoplasmic free Ca2+. This event may be crucial to the activation of Na/H exchange and subsequent DNA synthesis. Previous studies have implicated calmodulin (CaM) as a possible mediator of the effects of Ca2+ on these processes. here, we demonstrate that a specific CaM-dependent protein kinase (CaM-PK) system is rapidly activated in quiescent fibroblasts stimulated by a variety of mitogens. Cytoplasmic extracts of two human fibroblast cell types contained a major Ca2+-stimulated phosphoprotein of Mr 100,000 and pI 6.8 (Mr 100,000). This protein was shown by peptide mapping and immunological criteria to be identical to the prominent CaM-PK III substrate previously identified in a number of mammalian cells and tissues (Palfrey, H. C. (1983) FEBS Lett. 157, 183-190; Nairn, A.C., Bhagat, B., and Palfrey, H.C. (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 7939-7943). Stimulation of 32P-labeled serum-deprived fibroblasts with serum, individual growth factors (bradykinin, vasopressin, and epidermal growth factor), or Ca2+ ionophores resulted in a rapid 2- to 10-fold increase in the phosphorylation of Mr 100,000 as determined by immunoprecipitation using polyclonal antibodies. With serum or individual growth factors, the effect peaked at 0.5-1 min then declined back to base line within 5 min. Time course studies showed that the phosphorylation state of Mr 100,000 closely paralleled but lagged slightly behind the Ca2+ transient (measured with fura-2). Thus, dephosphorylation of Mr 100,000 must follow shortly after Ca2+ levels begin to decline. The effects of serum, bradykinin, and vasopressin on both the rise in intracellular Ca2+ and the phosphorylation of Mr 100,000 were independent of external Ca2+, whereas the effects of epidermal growth factor and A23187 required external Ca2+. Phosphorylation of Mr 100,000 in intact cells took place on threonine residues, a major portion occurring in the same major phosphopeptide found in the protein labeled in vitro. These results show that mitogenic activation of human fibroblasts leads to the binding of Ca2+ to CaM and the subsequent activation of CaM-dependent processes. 相似文献
44.
45.
Maria Benitez‐Guijarro Cesar Lopez‐Ruiz Žygimantė Tarnauskaitė Olga Murina Mahwish Mian Mohammad Thomas C Williams Adeline Fluteau Laura Sanchez Raquel Vilar‐Astasio Marta Garcia‐Canadas David Cano Marie‐Jeanne HC Kempen Antonio Sanchez‐Pozo Sara R Heras Andrew P Jackson Martin AM Reijns Jose L Garcia‐Perez 《The EMBO journal》2018,37(15)
46.
Clive Palfrey Yosef Kimhi U.Z. Littauer Roberta C. Reuben Paul A. Marks 《Biochemical and biophysical research communications》1977,76(3):937-942
Hexamethylene bisacetamide (HMBA), a potent inducer of erythroid differentiation in murine erythroleukemia cells (1), induces differentiation in mouse neuroblastoma cells, as indicated by the extension of neurites and the development of an excitable membrane. HMBA is effective at concentrations 50-fold lower than dimethylsulfoxide (2), another inducer of differentiation in both mouse neuroblastoma and murine erythroleukemia cells. 相似文献
47.
48.
Levi HC Makala 《Journal of biomedical science》2012,19(1):5
Pathogen persistence in immune-competent hosts represents an immunological paradox. Increasing evidence suggests that some
pathogens, such as, Leishmania major (L. major) have evolved strategies and mechanisms that actively suppress host adaptive immunity. If this notion is correct conventional
vaccination therapies may be ineffective in enhancing host immunity, unless natural processes that suppress host immunity
are also targeted therapeutically. The key problem is that the basis of pathogen persistence in immune-competent individuals
is unknown, despite decades of intense research. This fact, coupled with poor health care and a dearth of effective treatments
means that these diseases will remain a scourge on humans unless a better understanding of why the immune system tolerates
such infections emerges from research. Indoleamine 2,3-dioxygenase (IDO) has been shown to act as a molecular switch regulating
host responses, and IDO inhibitor drugs shown to possess potential in enhancing host immunity to established leishmania infections.
It is hoped that this review will help stimulate and help generate critical new knowledge pertaining to the IDO mechanism
and how to exploit it to suppress T cell mediated immunity, thus offer an innovative approach to studying the basis of chronic
leishmania infection in mice. 相似文献
49.
50.
Secretion: kiss and run caught on film 总被引:1,自引:0,他引:1
Recent results have provided graphic support for the hypothesis that vesicle secretion involves a 'kiss-and-run' mechanism. Evanescent field microscopy has shown that, during exocytosis, intravesicular markers escape without collapse of the vesicular membrane into the surface membrane and that the empty vesicle is immediately retrieved back into the cell. 相似文献