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Query: UNIPROT:P06889 (Mol)
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Monensin, like the lysosomotropic amines chloroquine and methylamine, caused a large accumulation of 125I-EGF in BALB/c-3T3 cells that was due to specific increases in the amount of intracellular intact hormone. However using a pulse-chase paradigm of 125I-EGF accumulation, marked differences were observed between monensin and the amines. When EGF was accumulated in the presence of monensin, there was a gradual loss of cell-bound radioactivity during a chase in the absence of the drug, and the labeled material recovered in the medium primarily consisted of degraded hormone. The continued presence of monensin in the chase medium substantively prevented the loss of cell bound material, and what little was recovered in the medium consisted of intact 125I-EGF. In contrast, when 125I-EGF was accumulated in the presence of methylamine, predominantly intact peptide was lost from the cells at a relatively high rate during the chase whether or not methylamine remained in the medium. When monensin was present in the chase medium following accumulation in the presence of either chloroquine or methylamine, the loss of intracellular 125I-EGF was essentially blocked.
Mol Cell Biochem 1987 Jan
PMID:Interaction between monensin and lysosomotropic amines in the regulation of the processing of epidermal growth factor by BALB/c 3T3 cells. 349 66

The actions of ionophores with different ion specificities and of thrombin on the release of 14C-labeled 5-hydroxytryptamine, [3H]noradrenaline, and endogenous ATP were measured in human platelets suspended in media with various K+ and Na+ concentrations. Besides thrombin, those ionophores [monensin, nigericin, and the combination of carbonylcyanide-p-trifluoromethoxyphenyl hydrazone (FCCP) with nonactin and/or valinomycin] which cause a rapid collapse of H+ gradients induced a fast and virtually total release of 14C-labeled 5-hydroxytryptamine and [3H]noradrenaline into the various media. FCCP alone, which causes an inversion of the membrane potential to inside negative values, induced a considerably slower amine release. Changes in the K+ and Na+ gradients did not lead to amine release, nor did interference with energy transduction by antimycin A with or without glycolysis inhibitors. Monensin and FCCP did not release ATP, whereas thrombin, added before or after incubation of platelets with FCCP and monensin, caused a marked liberation of the nucleotide. It is concluded that in intact human platelets (a) the intragranular storage of 5-hydroxytryptamine and noradrenaline mainly depends on the proton gradient across the granular membrane, and (b) ionophores causing a collapse of H+ gradients induce non-exocytotic release of 5-hydroxytryptamine and noradrenaline from intracellular storage granules.
Mol Pharmacol 1982 Jul
PMID:Storage of biogenic amines in intact blood platelets of man. Dependence on a proton gradient. 628 76

The influence of the polyether antibiotic Monensin on the rumen fermentation and the fattening results of fattening hybrids (genotype 61) and crossbreeding bulls of dairy cattle (genotype 19) was ascertained in two feeding experiments (E1 and E2). Caused by the supplementation of the antibiotic, the molar acetate quota decreased (1.9 to 4.8 Mol %) and the molar propionate concentration increased (0.2 to 2.9 Mol %) in the rumen fluid of crossbreeding bulls of dairy cattle and of fattening hybrids, it is, however, below the range described in literature. With the exception of the fattening hybrids in E1, the supplementation of Monensin resulted in the diminished intake of dry matter, the daily increase of the live weight of all groups of fattening bulls was higher (E1: fattening hybrids: 1106 resp. 1199g; crossbreeding bulls of dairy cattle: 1037 resp. 1058 g; E2: 997 resp. 1024 g; 895 resp. 981 g without resp. with Monensin). After the Monensin supplementation the crossbreeding bulls of dairy cattle showed a distinctly bigger decrease of the feed intake and a rise of the live weight increase than the fattening hybrids. For this reason the genotypes of dairy cattle showed in both experiments after the Monensin supplementation a bigger decrease of expenditure (0.8 resp. 7.1% and 5.6 resp. 11.3% in experiments 1 and 2) than the fattening hybrids.
 ...
PMID:[Effect of the polyether antibiotic "monensin" on the rumen fermentation and fattening results of crossbreeding bulls of dairy cattle and fattening hybrids]. 728 35

Stimulation of beta 2-adrenergic receptors in intact cells causes, first, rapid functional uncoupling from Gs, which is triggered by receptor phosphorylation, and, second, somewhat slower sequestration of the receptors to an internal compartment. The present study addresses a possible role of sequestration in the resensitization of desensitized beta 2-adrenergic receptors in human A431 cells. Exposure of these cells to isoproterenol caused rapid phosphorylation, desensitization (as assessed in adenylyl cyclase assays), and sequestration of the receptors. Subsequent removal of the agonist led to recycling of the receptors to the cell surface, dephosphorylation, and restoration of receptor function. These effects occurred without any change in the total receptor number. The rate constant of agonist-induced sequestration was 0.03/min; the rate constant of receptor recycling was 0.06/min and was not markedly altered by the presence of agonist. Blockade of sequestration with concanavalin A or 0.6 M sucrose prevented receptor dephosphorylation as well as receptor resensitization. Inhibition of protein phosphatases with calyculin A caused a similar blockade of beta 2-adrenergic receptor resensitization; the effects of maximally effective concentrations of concanavalin A and calyculin A were not additive. Monensin impaired recycling of desensitized beta 2-adrenergic receptors to the cell surface and also prevented receptor resensitization. We conclude that sequestration of beta 2-adrenergic receptors, followed by dephosphorylation and recycling to the cell surface, may serve to restore the function of desensitized receptors.
Mol Pharmacol 1995 Apr
PMID:Sequestration and recycling of beta 2-adrenergic receptors permit receptor resensitization. 772 28

1. Alzheimer's disease is characterized by the deposition in the brain of extracellular amyloid plaques and vascular deposits consisting mostly of amyloid beta-peptide (A beta). A beta, a polypeptide of 39-43 amino acids (M(r), approximately 4 kDa), is derived proteolytically from a family of proteins of 695-770 amino acids (M(r), approximately 110-140 kDa) called beta-amyloid precursor protein (beta APP). 2. beta APP, an integral membrane glycoprotein, is extensively posttranslationally modified within the endoplasmic reticulum (ER) and various Golgi compartments. beta APP is cleaved by proteases in either the trans-Golgi network or the post-Golgi apparatus and then secreted as a truncated soluble form into the conditioned media of cultured cells and cerebrospinal fluid samples from human subjects. beta APP can be processed either by an antiamyloidogenic secretory pathway or by an endosomal/lysosomal pathway. 3. I studied the effect of two ionophores on the processing of beta APP in cultured cells. Monensin and, in some cases, ammonium chloride increase the intracellular accumulation of beta APP in several cell lines and may alter its processing. Monensin, which had the most consistent effects, also inhibited secretion of beta APP in a differentiated (growth factor mediated) cell line. Nigericin, with greater K+ selectivity, was less able to alter the accumulation and possible processing of the protein. 4. These results suggest that the increase in the accumulation of intracellular beta APP observed after treating cells with ionophores has some specificity. The selective effect of these ionophores on the metabolism of beta APP may provide a model system to analyze the pathways for studying maturation, secretion, and degradation of beta APP.
Cell Mol Neurobiol 1994 Aug
PMID:Effect of ionophores on the processing of the beta-amyloid precursor protein in different cell lines. 778 40

We have investigated the role of a rest-dependent inotropic factor in determining species-related differences in cardiac force-frequency relationships (FFR). Isolated rat, rabbit or guinea-pig papillary muscles, as well as guinea-pig ventricular myocytes were superfused with 1.8 mM Ca2+ Tyrode. In rat muscles, isometric force amplitude decreased, while in rabbit or guinea-pig muscles force increased with frequency (0.02-1 Hz). Paired-pulse pacing potentiated contraction markedly at all frequencies in rabbit muscles, but not at low frequencies in rat muscles. We tested the hypothesis that high intracellular Na+ levels (Nai) are responsible for negative FFR. The ionophore monensin increased Nai, reversed the FFR of rabbit and guinea-pig muscles from positive to negative, by increasing force mostly at low frequencies, and decreased the paired-pulse potentiation of contraction at low frequencies. Monensin added during rest also reversed rest-induced decay. In isolated myocytes, monensin had qualitatively similar effects on cell shortening as well as on Cai transients. Monensin also decreased the action potential duration (APD) but did not change the pattern of its variation with frequency. Cells intracellularly dialyzed with 20 mM Na+ via a patch pipette also showed rest potentiation of the Cai transients, in contrast to cells dialyzed with 10 mM Na+, which showed rest decay of the transients. APD was also shorter in myocytes dialyzed with 20 mM Na+ than in those dialyzed with lower Na+. The results indicate that in the presence of high Nai, sarcoplasmic reticular Ca2+ load is increased during diastole, possibly via reverse-mode Na+/Ca2+ exchange, and therefore that Nai is an important factor determining the FFR. In addition, the data suggest that short APDs in preparations showing negative FFR may be partly a consequence of increased Nai.
J Mol Cell Cardiol 1997 Mar
PMID:Monensin-induced reversal of positive force-frequency relationship in cardiac muscle: role of intracellular sodium in rest-dependent potentiation of contraction. 915 59

We have characterized the biosynthetic origin of somatostatin-14 (SS-14), SS-28, and pro-SS[1-10] from pro-SS (PSS) in 1027B2 rat islet tumor cells. Because these cells lack regulated secretion and show unresponsiveness of the SS gene to cAMP, we have additionally carried out morphological and functional studies to elucidate the molecular defect in cAMP signalling and to localize the sites of PSS maturation along the secretory pathway. Cell extracts and secretion media were analysed by high performance liquid chromatography and specific C- and N-terminal radioimmunoassays. Electron microscopic sampling of 1027B2 cell cultures showed that most cells had very few dense core secretory granules for heterogeneous sizes. The cells expressed the endoproteases furin, PC1, and PC2 and contained large quantities of fully processed SS-14 and SS-28 with very little unprocessed PSS (ratio SS-14:SS-28:PSS = 39:51:10%). They secreted high concentrations of SS-14, SS-28, and PSS[1-10] constitutively along with PC1 and PC2. Pulse-chase studies demonstrated that PSS is rapidly (within 15 min), and efficiently processed to SS-14, SS-28, and PSS[1-10] via separate biosynthetic pathways: PSS --> SS-14 + 8 kDa; PSS --> SS-28 + 7 kDa; PSS --> PSS[1-10]. Monensin reduced intracellular SS-like immunoreactivity without altering processing efficiency. Transfection with the catalytic subunit of protein kinase A (PKA-C) activated SS promoter-CAT activating indicating that the defect in cAMP-dependent signaling in 1027B2 cells lies at the level of PKA-C. PKA-C overexpression failed to alter the ratio of processed SS-14 and SS-28. These results demonstrate that SS-14, SS-28, and PSS[1-10] are independently synthesized from PSS and that efficient precursor processing can occur within the constitutive secretory pathway in the relative absence of dense core secretory vesicles.
Mol Cell Endocrinol 1997 Aug 08
PMID:Somatostatin-14, somatostatin-28, and prosomatostatin[1-10] are independently and efficiently processed from prosomatostatin in the constitutive secretory pathway in islet somatostatin tumor cells (1027B2). 929 77

The extensive remodelling of the human endometrium throughout the menstrual cycle is accompanied by changes in production of matrix metalloproteinases, the activity of which can be inhibited by specific tissue inhibitors or by tissue inhibitors of metalloproteinases (TIMP)s with a 1:1 stoichiometry. This study immunolocalized TIMP-1, TIMP-2 and TIMP-3 in dated normal human endometrium across the menstrual cycle and examined cultured endometrial cells for their production. All three TIMPs were present in the major cellular compartments, luminal epithelium, glands, stroma, endothelial cells and vascular smooth muscle cells with the most intense immunoreactivity in the luminal epithelium. TIMP-1 and -3 were lower in the mid-to-late proliferative phase with a nadir of TIMP-3 particularly in the late proliferative phase. Decidualized stromal cells stained strongly positive for TIMP-1, -2 and -3. Cells of haematopoietic origin never stained. Monensin treatment of tissue resulted in accumulation of TIMPs in all cellular compartments but particularly of TIMP-1 in epithelium. Cultured endometrial stromal cells released more TIMP-1 than TIMP-2 or TIMP-3 into culture medium and all were increased following decidualization in vitro. Epithelial cells in culture produced less TIMPs than stromal cells, and only a few epithelial cells in each culture were immunopositive for TIMP-1. The ubiquitous distribution of TIMPs implicates them in maintenance of endometrial integrity, with changes in the matrix metalloproteinases without concomitant changes in TIMPs determining endometrial matrix degradation.
Mol Hum Reprod 1997 Sep
PMID:Tissue inhibitor of metalloproteinases (TIMP)-1, -2 and -3 in human endometrium during the menstrual cycle. 935 97

The toxicity of two conjugates containing ribosome-inactivating proteins (RIPs, i.e. saporin and ricin-A chain x-linked to transferrin) has been measured on a prostatic cancer line (PC3) naturally overexpressing the transferrin receptor, in the presence of monensin and chloroquine. This paper investigates whether the increased toxicity of Tf-RIPs induced by monensin and chloroquine may be due to alterations of the normal endocytotic pathway of the complexes mediated by the transferrin receptor. Monensin, besides inducing alkalinization of normally acid intracellular compartments, causes an accumulation of the receptor-bound Tf-RIP in a perinuclear region contiguous to the cisternae of the trans-Golgi network. Chloroquine, though increasing the intracellular pH, seems not to modify the endocytotic pathway of these chimeric molecules. We believe that the enhanced toxicity of the Tf-RIPs may be related to intracellular alkalinization (i.e., endosomal or lysosomal pH) rather than to the effects on the recycling of transferrin receptor-bound toxins. We conclude that the efficacy of chimeric toxins may be modulated not only by the carrier used for their engineering but also by addition of drugs able to influence the stability and activation of the toxins inside the cell.
Cell Mol Life Sci 1998 Aug
PMID:The effect of monensin and chloroquine on the endocytosis and toxicity of chimeric toxins. 976 Sep 93

Human synovial endothelial cell (HSE) intracellular adhesion molecule-1 (ICAM-1) is upregulated maximally by synergy of tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma). Such synergy is not as pronounced in human umbilical vein endothelium (HUVE). ICAM surface staining and ELISA detection reflected similar levels on HUVE and HSE cells, yet mRNA levels were much higher in HSE cells in response to TNF alpha/IFN gamma. To correlate protein and mRNA levels of ICAM-1, both cell types were permeabilized and stained with a monoclonal antibody against ICAM-1. HSE cells displayed a distinct vesicular cytoplasmic staining for ICAM while HUVE cells were devoid of such stained vesicles upon staining with the antibody. ICAM-1 immunostaining of HSE cytoplasmic vesicles appeared enhanced in cells treated with TNF alpha/IFN gamma and monensin, an endosomal processing inhibitor. Monensin inhibited HSE cell surface expression of ICAM-1 routinely up to 70%, while HUVE cell expression was unaffected. In addition, monensin also inhibited soluble ICAM-1 release from HSE cells while not effecting HUVE cells. Immunoprecipitation of ICAM-1 followed by gel electrophoresis indicated that HUVE and HSE cell ICAMs are expressed in cell-specific forms. These results define distinct forms and distinct secretory pathways for ICAM-1 in HSE cells and HUVE cells that indicate functional differences between these human endothelia.
Cell Mol Biol (Noisy-le-grand) 1999 Feb
PMID:Distinct ICAM-1 forms and expression pathways in synovial microvascular endothelial cells. 1009 42


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