Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sulfonylureas are a class of drugs widely used to promote insulin secretion in the treatment of non-insulin-dependent diabetes mellitus. These drugs interact with the sulfonylurea receptor of pancreatic beta cells and inhibit the conductance of adenosine triphosphate (ATP)-dependent potassium (KATP) channels. Cloning of complementary DNAs for the high-affinity sulfonylurea receptor indicates that it is a member of the ATP-binding cassette or traffic ATPase superfamily with multiple membrane-spanning domains and two nucleotide binding folds. The results suggest that the sulfonylurea receptor may sense changes in ATP and ADP concentration, affect KATP channel activity, and thereby modulate insulin release.
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PMID:Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. 771 39

Potassium (K) channels regulate cellular excitability. Their opening hyperpolarises the membrane potential and induces quiescence whereas their closure produces depolarisation and excitation. One K-channel superfamily includes the delayed rectifier (KV), the A-type (KA) and the large conductance, Ca-sensitive (BKCa) channels. These serve to terminate excitatory events and consist of a tetramer of alpha-subunits each comprising six transmembrane-spanning segments including a voltage-sensor. Additional beta-subunits which modify inactivation and voltage sensitivity may also be present. Channels in the second superfamily include the inward rectifiers (KIR) and the ATP-sensitive K-channel (KATP). Their tetrameric assembly of alpha-subunits contains only two transmembrane-spanning segments and lacks a voltage sensor. KATP is associated with a sulphonylurea binding site belonging to the ATP-binding cassette family. Although KIR conducts poorly at potentials positive to EK, both it and KATP do conduct over the physiological potential range. K-channel modulators are important in determining channel function. These include drugs like tetraethylammonium and 4-aminopyridine and more recently-discovered selective agents active at KATP and BKCa. These are typified by diazoxide, levcromakalim and glibenclamide and by NS1619, iberiotoxin and penitrem A, respectively.
Diabetes Res Clin Pract 1995 Aug
PMID:The role of potassium channels in excitable cells. 852 20

Micromolar concentrations of tolbutamide will inhibit (SUR1/K(IR)6. 2)(4) channels in pancreatic beta-cells, but not (SUR2A/K(IR)6.2)(4) channels in cardiomyocytes. Inhibition does not require Mg(2+) or nucleotides and is enhanced by intracellular nucleotides. Using chimeras between SUR1 and SUR2A, we show that transmembrane domains 12-17 (TMD12-17) are required for high-affinity tolbutamide inhibition of K(ATP) channels. Deletions demonstrate involvement of the cytoplasmic N-terminus of K(IR)6.2 in coupling sulfonylurea-binding with SUR1 to the stabilization of an interburst closed configuration of the channel. The increased efficacy of tolbutamide by nucleotides results from an impairment of their stimulatory action on SUR1 which unmasks their inhibitory effects. The mechanism of inhibition of beta-cell K(ATP) channels by sulfonylureas during treatment of non-insulin-dependent diabetes mellitus thus involves two components, drug-binding and conformational changes within SUR1 which are coupled to the pore subunit through its N-terminus and the disruption of nucleotide-dependent stimulatory effects of the regulatory subunit on the pore. These findings uncover a molecular basis for an inhibitory influence of SUR1, an ATP-binding cassette (ABC) protein, on K(IR)6.2, a ion channel subunit.
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PMID:The tolbutamide site of SUR1 and a mechanism for its functional coupling to K(ATP) channel closure. 1052 67

1. Glibenclamide, a sulphonylurea widely used for the treatment of non-insulin-dependent diabetes mellitus, has been shown to inhibit the activities of various ATP-binding cassette (ABC) transporters. In the present study, its effects towards multidrug resistance protein 1 (MRP1), an ABC efflux pump conferring multidrug resistance and handling organic anions, were investigated. 2. Intracellular accumulation of calcein, an anionic dye substrate for MRP1, was strongly increased by glibenclamide in a dose-dependent manner in MRP1-overexpressing lung tumour GLC4/Sb30 cells through inhibition of MRP1-related calcein efflux. By contrast, glibenclamide did not alter calcein levels in parental control GLC4 cells. Another sulphonylurea, tolbutamide, was however without effect on calcein accumulation in both GLC4/Sb30 and GLC4 cells. 3. Glibenclamide used at 12.5 microM was, moreover, found to strongly enhance the sensitivity of GLC4/Sb30 cells towards vincristine, an anticancer drug handled by MRP1. 4. Efflux of carboxy-2',7'-dichlorofluorescein, an anionic dye handled by the ABC transporter MRP2 sharing numerous substrates with MRP1 and expressed at high levels in liver, was also strongly inhibited by glibenclamide in isolated rat hepatocytes. 5. In summary, glibenclamide reversed MRP1-mediated drug resistance likely through inhibiting MRP1 activity and blocked organic anion efflux from MRP2-expressing hepatocytes. Such effects associated with the known inhibitory properties of glibenclamide towards various others ABC proteins suggest that this sulphonylurea is a general inhibitor of ABC transporters.
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PMID:The sulphonylurea glibenclamide inhibits multidrug resistance protein (MRP1) activity in human lung cancer cells. 1115 31

The role of ATP-binding cassette (ABC) proteins such as multidrug resistance-associated proteins (MRPs) is critical in drug resistance in cancer cells and in plant detoxification processes. Due to broad substrate spectra, specific modulators of these proteins are still lacking. Sulfonylureas such as glibenclamide are used to treat non-insulin-dependent diabetes since they bind to the sulfonylurea receptor. Glibenclamide also inhibits the cystic fibrosis transmembrane conductance regulator, p-glycoprotein in animals and guard cell ion channels in plants. To investigate whether this compound is a more general blocker of ABC transporters the sensitivity of ABC-type transport processes across the vacuolar membrane of plants and yeast towards glibenclamide was evaluated. Glibenclamide inhibits the ATP-dependent uptake of beta-estradiol 17-(beta-D-glucuronide), lucifer yellow CH, and (2',7'-bis-(2-carboxyethyl)-5-(and-6-)carboxyfluorescein. Transport of glutathione conjugates into plant but not into yeast vacuoles was drastically reduced by glibenclamide. Thus, irrespective of the homologies between plant, yeast and animal MRP transporters, specific features of plant vacuolar MRPs with regard to sensitivity towards sulfonylureas exist. Glibenclamide could be a useful tool to trap anionic fluorescent indicator dyes in the cytosol.
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PMID:Differential sensitivity of plant and yeast MRP (ABCC)-mediated organic anion transport processes towards sulfonylureas. 1459 8

Advances in understanding the overall structural features of inward rectifiers and ATP-binding cassette (ABC) transporters are providing novel insight into the architecture of ATP-sensitive K+ channels (KATP channels) (KIR6.0/SUR)4. The structure of the K(IR) pore has been modeled on bacterial K+ channels, while the lipid-A exporter, MsbA, provides a template for the MDR-like core of sulfonylurea receptor (SUR)-1. TMD0, an NH2-terminal bundle of five alpha-helices found in SURs, binds to and activates KIR6.0. The adjacent cytoplasmic L0 linker serves a dual function, acting as a tether to link the MDR-like core to the KIR6.2/TMD0 complex and exerting bidirectional control over channel gating via interactions with the NH2-terminus of the KIR. Homology modeling of the SUR1 core offers the possibility of defining the glibenclamide/sulfonylurea binding pocket. Consistent with 30-year-old studies on the pharmacology of hypoglycemic agents, the pocket is bipartite. Elements of the COOH-terminal half of the core recognize a hydrophobic group in glibenclamide, adjacent to the sulfonylurea moiety, to provide selectivity for SUR1, while the benzamido group appears to be in proximity to L0 and the KIR NH2-terminus.
Diabetes 2004 Dec
PMID:Toward linking structure with function in ATP-sensitive K+ channels. 1556 97

The human ATP-binding cassette (ABC) protein MRP1 causes resistance to many anticancer drugs and is also a primary active transporter of conjugated metabolites and endogenous organic anions, including leukotriene C(4) (LTC(4)) and glutathione (GSH). The sulfonylurea receptors SUR1 and SUR2 are related ABC proteins with the same domain structure as MRP1, but serve as regulators of the K(+) channel Kir6.2. Despite their functional differences, the activity of both SUR1/2 and MRP1 can be blocked by glibenclamide, a sulfonylurea used to treat diabetes. Residues in the cytoplasmic loop connecting transmembrane helices 15 and 16 of the SUR proteins have been implicated as molecular determinants of their sensitivity to glibenclamide and other sulfonylureas. We have now investigated the effect of mutating Tyr(1189) and Tyr(1190) in the comparable region of MRP1 on its transport activity and sulfonylurea sensitivity. Ala and Ser substitutions of Tyr(1189) and Tyr(1190) caused a > or =50% decrease in the ability of MRP1 to transport different organic anions, and a decrease in LTC(4) photolabeling. Kinetic analyses showed the decrease in GSH transport was attributable primarily to a 10-fold increase in K(m). In contrast, mutations of these Tyr residues had no major effect on the catalytic activity of MRP1. Furthermore, the mutant proteins showed no substantial differences in their sensitivity to glibenclamide and tolbutamide. We conclude that MRP1 Tyr(1189) and Tyr(1190), unlike the corresponding residues in SUR1, are not involved in its differential sensitivity to sulfonylureas, but nevertheless, may be involved in the transport activity of MRP1, especially with respect to GSH.
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PMID:Role of two adjacent cytoplasmic tyrosine residues in MRP1 (ABCC1) transport activity and sensitivity to sulfonylureas. 1565 36

ATP-sensitive potassium (K(ATP)) channels are heterooctamers of an inward rectifier potassium channel (Kir6) and a sulfonylurea receptor (SUR, a member of the ATP-binding cassette (ABC) transporter family). In the pancreatic beta-cell K(ATP) channels are dynamically active, and transgenic expression of overactive Kir6.2 mutants leads to severe neonatal diabetes and death, while in the ventricular cardiomyocyte they are closed except under conditions of severe metabolic inhibition, and similarly overactive transgenes are without gross phenotypic consequence. This discrepancy may arise in part from differences at the molecular level between the two SUR isotypes that constitute the regulatory subunit of the K(ATP) channel in those tissues: SUR1 in the pancreas, SUR2A in the heart. K(ATP) channels generated from coexpression of Kir6.2 with SUR1 exhibit greater MgADP stimulation than channels generated from coexpression of Kir6.2 with SUR2A. This difference persists when the open state stability of the channel is enhanced by application of PIP(2), consistent with each isotype transducing an intrinsically different energetic contribution to the channel pore. When expressed as isolated, affinity-purified protein constructs, NBF2 of SUR1 exhibits increased in vitro ATP hydrolysis compared to NBF2 of SUR2A. This biochemical difference may underlie the increased MgADP stimulation exhibited by SUR1-containing channels vs. SUR2A-containing channels, which may in turn contribute to physiological differences, observed at the tissue level, between pancreatic and cardiac K(ATP) channels.
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PMID:Differential nucleotide regulation of KATP channels by SUR1 and SUR2A. 1589 23

Acarbose, a pseudomaltotetraose, is produced by strains of the genus Actinoplanes. The compound is an inhibitor of alpha-glucosidases and is used in the treatment of patients suffering from type II diabetes. The benefits of acarbose for the producer are not known; however, a role as carbophor has been proposed. Acarbose synthesis is induced in the presence of maltose and maltotriose. We have investigated the transport activities for these sugars in Actinoplanes sp. strain SN 223/29 grown on different carbon sources, including acarbose. Under the conditions used, Actinoplanes sp. utilized acarbose as sole source of carbon and energy, although growth ceased after 24 h, possibly due to the accumulation of a toxic degradation product in the cytosol. Maltose transport was observed in cells grown on each of the substrates tested except glucose. Maltose transport of acarbose-grown cells was inhibited by sucrose and trehalose and, to a lesser extent, by maltodextrins but not by acarbose. In contrast, in maltose/maltotriose-grown cells maltose uptake was inhibited by acarbose. Maltotriose uptake in these cells was less inhibited by maltose but was more sensitive to acarbose than in acarbose-grown cells. The Km and Vmax values of maltose uptake are in the range of those reported for binding protein-dependent sugar ATP-binding cassette (ABC) transport systems. A maltose-binding protein that does not bind acarbose was isolated from cells grown on either acarbose, glycerol or maltose. These results suggest that an acarbose-insensitive maltose/sucrose/trehalose transporter that also accepts maltodextrins operates in acarbose-grown cells while a maltodextrin transporter that accepts maltose/sucrose/trehalose and is moderately sensitive to acarbose is found in cells grown in maltose/maltotriose-containing media.
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PMID:Characterization of maltose and maltotriose transport in the acarbose-producing bacterium Actinoplanes sp. 1593 74

ATP-binding cassette (ABC) transporters are involved in a variety of physiologic processes such as xenobiotic defense, lipid metabolism, ion homeostasis and immune functions. A large number of ABC proteins have been causatively linked to rare and common human genetic diseases including familial high-density lipoprotein deficiency, retinopathies, cystic fibrosis, diabetes and cardiomyopathies. Furthermore, genetic variations in ABC transporter genes and dysregulated expression patterns of these molecules significantly contribute to drug resistance in human cancer cells and alter the pharmacokinetic properties of a variety of drugs. In order to analyze DNA sequence alterations or define disease-associated mRNA expression patterns of the complete ABC transporter superfamily, novel high-throughput molecular methods such as quantitative real-time PCR and DNA microarray analysis are emerging. The aim of this review is to provide an overview and to present some examples of human ABC transporters involved in monogenic diseases, cancer and pharmacogenetics. Methodologic aspects of molecular diagnostics applied to analyze genetic variations, mRNA and protein expression levels and functional characteristics of ABC transporters are discussed.
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PMID:Molecular diagnosis of ATP-binding cassette transporter-related diseases. 1614 78


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