Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binding of beraprost sodium (sodium dl-4-[(1R,2R,3aS,8bS)-1,2,3a,8b-tetrahydro-2-hydroxy-1-[(3S, 4RS)- 3-hydroxy-4-methyl-oct-6-yne-(E)-1-enyl] -5- cyclopenta[b]benzofuranyl]butyrate, TRK-100), a new potent antithrombotic agent, to washed platelets of humans and rats was studied. [11-3H]-TRK-100 binding was rapid, reversible, saturable, and highly specific. Scatchard analysis of concentration-dependent binding to human platelets revealed a single class of specific binding sites with an equilibrium dissociation constant (Kd) of 133 nmol/l and a maximal concentration of binding sites (Bmax) of 46 fmol/10(8) platelets (275 sites/cell). Similar binding was observed on rat platelets. The Kd and Bmax were 66 nmol/l and 124 fmol/10(8) platelets (750 sites/cell), respectively. Competitive studies indicated that TRK-100 was 1.5 times less active than prostacyclin (epoprostenol, PGI2), but was 3 times more potent than PGE1 in displacing [3H]-TRK-100 from the binding sites on rat platelets. PGE2, PGD2, PGF2 alpha, and pinane thromboxane A2, a stable thromboxane A2 analogoue, had no affinity for the binding sites. The relative affinity of the four enantiomers of TRK-100--APS-314d, 315d, 3141 and 3151--for the binding sites was 100: 14: less than 1: less than 1, respectively. These results suggest that TRK-100 is a useful tool for studying biological roles of PGI2 as well as for use as an antithrombotic agent since TRK-100 mimics its actions via specific interaction with PGI2 receptors.
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PMID:Specific binding of the new stable epoprostenol analogue beraprost sodium to prostacyclin receptors on human and rat platelets. 266 58

Effect of beraprost sodium (TRK-100), a stable PGI2 analog, on experimentally induced skin ulcer was studied in rats. An experimental skin ulcer was developed by intradermal injection of acetic acid. Injection of glacial acetic acid to the skin in the left hind leg instep of rats resulted in the necrosis of the skin, and a skin ulcer developed in 3 days. The ulcer area reached its peak on the 5th day, and recovered to its control level within 4 weeks. The effects of TRK-100 and indomethacin on the ulcer were tested. TRK-100 showed suppressive effects on the development of the ulcer. A dose of 30 micrograms/kg (p.o.) accelerated healing of the ulcer when scored macroscopically on the 9th or 15th day. At a dose of 100 micrograms/kg (p.o.), it reduced the development of the ulcer and accelerated healing with statistical significance from the 5th day and thereafter. Indomethacin also reduced the development of the ulcer and accelerated healing with statistical significance from the 7th day and thereafter. These results suggest TRK-100 may be effective on the inhibition of the development and accelerated the healing of the skin ulcer formed in various pathological states.
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PMID:Effect of beraprost sodium (TRK-100) on acetic acid-induced skin ulcer. 267 30

The effects of epidermal growth factor (EGF) on membrane potential were investigated in suspensions of the following three cell types endowed with a large complement of specific receptors: EGFR-T17 (a clone of mouse NIH-3T3 fibroblasts overexpressing EGF receptors); A431 and KB (two human carcinoma lines). In all these lines EGF induced a rapid and marked hyperpolarization constituted by an initial peak (in all three cell lines) and a subsequent sustained plateau phase, concomitant with the well-known increase of [Ca2+]i. The time course and phorbol ester inhibitability of the membrane potential effects were the same as for the [Ca2+]i response. Experiments with Na+-free and chloride-free media excluded a major role of the latter ions in the EGF-induced hyperpolarization. In contrast, experiments with high K+ media, with the monovalent cation ionophore gramicidin and with Ca2+-free media together with either a Ca2+ ionophore (ionomycin, in A431 and EGFR-T17), or an agonist (bradykinin, in A431) addressed to a receptor coupled to phosphoinositide hydrolysis, were consistent with the involvement of Ca2+-activated K+ channels. The EGF-induced hyperpolarization was completely blocked by the K+ channel blocker, quinidine, and unaffected by a variety of other drugs. Patch clamping of individual EGFR-T17 cells confirmed the initial hyperpolarization (from approximately -30 mV, the resting potential, to -60, -80 mV) was due to activation of an outward current. This initial hyperpolarization was followed by fluctuations (period approximately 1 min) persisting as long as the cells could be analyzed. Thus, the changes of membrane potential appear to be not only novel members of the group of early events triggered by EGF in target cells but also long-lasting effects of the growth factor, which continue for unexpectedly long periods of time after EGF application.
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PMID:The effect of epidermal growth factor on membrane potential. Rapid hyperpolarization followed by persistent fluctuations. 278 95

The effect of a 40 minute thermoneutral bath on diuretic function and blood volume in a total of 27 pregnant women (13 healthy and 14 pregnant women with edema rsep. EPH-gestosis) was investigated. In both groups water immersion led to a significant increase of urine flow, natriuresis, kaliuresis, osmotic and free water clearance. Plasma volume increased about 8-9%. The patients with gestosis showed a higher creatinine clearance. The same group also showed a higher osmotic clearance and relatively more sodium excretion. Regarding the flushing effect of bath, two mechanism of water immersion that originated in hydrostatic pressure have to be discussed-activation of renal functions and mobilisation of interstitial fluid.
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PMID:[The diuretic effect of a bath. Study in healthy pregnant females and patients with edema and gestosis]. 280 Jul 72

Sodium vanadate activates "in vitro" insulin receptor autophosphorylation and protein tyrosine kinase in a dose-dependent manner. Insulin receptor protein tyrosine kinase is directly activated also by the anti-insulin receptor beta subunit monoclonal antibody 18-44. We previously demonstrated that the anti-insulin receptor monoclonal antibody MA-10 decreases insulin-stimulated receptor protein tyrosine kinase activity "in vitro", without inhibiting insulin receptor binding. In this report we show that insulin receptor protein tyrosine kinase, activated by sodium vanadate or by monoclonal antibody 18-44, is inhibited by MA-10 antibody. These data suggest that insulin receptor protein tyrosine kinase activity can be either activated and inhibited through mechanisms different from insulin binding.
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PMID:Direct modulation of insulin receptor protein tyrosine kinase by vanadate and anti-insulin receptor monoclonal antibodies. 283 89

The human apolipoproteins are secretory proteins some of which have been shown to undergo proteolytic processing and post-translational addition of carbohydrate. Apolipoprotein A-I (apo-A-I), the predominant protein associated with high density lipoproteins, undergoes co-translational proteolytic processing as well as post-translational conversion of proapo-A-I to mature apo-A-I following cellular secretion. Utilizing the human hepatoma cell line HEP-G2, we have established that, in addition to proteolytic processing, secreted nascent apo-A-I is acylated with palmitate. Uniformly labeled [14C]palmitate and [1-14C]palmitate were each incorporated into apo-A-I when analyzed by sodium dodecyl sulfate gel electrophoresis and autoradiography. The acylation of apo-A-I with palmitate was confirmed by immunoprecipitation and gas chromatography/mass spectrometry. Hydroxylamine treatment resulted in the deacylation of apo-A-I. Although three of the apo-A-I isoforms analyzed by two-dimensional gel electrophoresis were shown to contain radio-labeled palmitate, 80% of acylated apo-A-I was in the proapolipoprotein A-I isoform. [14C]Oleate was not incorporated in secreted apo-A-I, indicating the specificity of the acylation of apo-A-I. Incubation of [14C] palmitate-acylated apo-A-I in serum and plasma under conditions in which proapo-A-I is proteolytically cleaved to mature apo-A-I did not result in deacylation. These data establish that fatty acid acylation occurs in human secretory proteins in addition to the previously reported acylation of cellular membrane proteins. These results suggest that the covalent linkage of lipids to apolipoproteins may play a critical role in apolipoprotein and lipoprotein metabolism.
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PMID:Human apolipoprotein A-I. Post-translational modification by fatty acid acylation. 300 8

Saturation experiments of the highly potent cholecystokinin analogue [3H]Boc(diNle28,31)CCK27-33 ([3H]BNDL-CCK7, 100 Ci/mmol) with guinea pig brain cortex in a large concentration range (0.05 nM to 30 nM) show the presence of two different binding sites (A site: KD = 0.13 nM, Bmax = 35 fmol/mg; B site: KD = 6.4 nM, Bmax = 92 fmol/mg). Both sites exhibit different sensitivity to sodium ions and therefore can be selectively investigated at [3H]BDNL-CCK7 concentration lower than 1 nM for the A site in Tris buffer and in Krebs buffer for the B site. The selectivity factors KIB/KIA of various CCK related peptides vary from 58 for CCK4 to 26 for CCK8 and 4 for the antagonist (Nle28,31) CCK27-32-NH2. The occurrence of two different CCK binding sites in the brain could explain biphasic pharmacological effects of CCK8.
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PMID:Occurrence of two cholecystokinin binding sites in guinea-pig brain cortex. 301 38

To clone the gene for the human Na+/H+ antiporter, we first constructed a stable mouse LTK- cell line (LAP1) lacking Na+/H+ antiport activity. Second, we devised a selective technique based on acid killing that specifically sorts out cells expressing low levels of Na+/H+ antiport activity from a population of antiporter-deficient cells (AP-). LAP1 cells (TK- and AP-) were cotransformed with human genomic DNA and the thymidine kinase (TK) gene. TK+ transformants, first selected, were submitted to acid loading. The rare transformants that survived (frequency, 2-8 X 10(-7) expressed Na+/H+ antiport activity (AP+). We found that: transformation with mouse LAP1 DNA did not give rise to AP+ transformants; transformation of LAP1 cells with DNA from an altered Na+/H+ antiporter hamster variant led to AP+ transformants expressing the altered Na+/H+ antiporter of the DNA donor; human repeated sequences were present in all primary, secondary, and tertiary mouse AP+ transformants; six identical EcoRI human DNA fragments (55 kilobase pairs of the human genome) cosegregated with the Na+/H+ antiport activity in secondary and tertiary transformants. These results strongly suggest that we have stably expressed the structural gene for the human Na+/H+ antiporter in mouse cells.
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PMID:Functional expression of a human Na+/H+ antiporter gene transfected into antiporter-deficient mouse L cells. 302 40

Kidneys were perfused either with Euro-Collins-solution or with HTK-solution of Bretschneider. The perfusion pressure as well as the perfusion flow were measured during a six-minute perfusion. The perfusion resistance was higher in Euro-Collins-kidneys than during HTK-perfusion. The venous outflow of the kidney as well as the ureteral outflow was measured during each minute of the perfusion and has analysed for osmolality, and for sodium and potassium concentrations. In Euro-Collins-kidneys a complete "equilibration" of the extracellular space was not achieved, while during HTK-perfusion concentrations in the venous as in the tubular outflow, similar to those in the HTK-solution itself, could be reached. At the end of the different perfusions, tissue was analysed for biochemical parameters such as ATP, ADP, AMP and lactate as well as for morphological features. Lactate had increased and ATP had decreased during perfusion with Euro-Collins-solution, while ATP had not changed and lactate had decreased during perfusion with HTK-solution. Normal glomerular, tubular and dilated vascular structures can be seen after HTK-perfusion, while a glomerular and vascular contraction takes place during Euro-Collins-perfusion.
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PMID:Short-term perfusion and "equilibration" of canine kidneys with protective solutions. 310 3

Intact human neutrophils hydrolyzed N-formyl-Met-Leu-[3H]Phe (fMLP) and released Leu-[3H]Phe, cleaving 45-50% of the peptide within 20 min at 37 degrees C. The dipeptide after its release was then hydrolyzed to free amino acids by a dipeptidase (EC 3.4.13.11). This activity, present in plasma membrane-enriched fractions of neutrophil lysates, was also inhibited over 90% by phosphoramidon, an inhibitor of neutral endopeptidase (NEP, EC 3.4.24.11). Dithiothreitol and EDTA inhibited the activity to a comparable degree, suggesting the requirement for a heavy metal cofactor. Bestatin and amastatin, inhibitors of aminopeptidases (but not human kidney NEP), did not inhibit the rate of fMLP degradation but prevented the production of free phenylalanine and enhanced the accumulation of Leu-Phe. Of other inhibitors, alpha 1-antitrypsin and alpha 2-macroglobulin slightly enhanced the rate of fMLP hydrolysis by neutrophils, and others tested were ineffective. Rabbit antiserum to homogeneous human kidney NEP reacted specifically with a 100-kDa protein present in sodium dodecyl sulfate-solubilized neutrophils. The Mr of this protein was slightly larger than that of the kidney enzyme in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The antiserum incubated with intact cells specifically inhibited the degradation of fMLP over 70%. First, we confirm that NEP present on the plasma membrane cleaves fMLP at the Met-Leu bond; then the dipeptide Leu-Phe is cleaved by a dipeptidase. Finally, inhibition of NEP completely blocks fMLP-mediated chemotaxis. Thus, the enzyme may play an important role in modulating chemotactic responses.
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PMID:Function of neutral endopeptidase on the cell membrane of human neutrophils. 328 36


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