Structural requirements of sulphonylureas and analogues for interaction with sulphonylurea receptor subtypes

Meyer, Miriam; Chudziak, Franz; Schwanstecher, Christina; Schwanstecher, Mathias; Panten, U.

doi:10.1038/sj.bjp.0702763

Cited by 41 publications

(38 citation statements)

References 36 publications

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“…Certain pharmacological agents that increase insulin secretion, such as sulfonylureas and meglitinides, block K ATP channel activity by binding directly to the SUR1 subunit, and lead to depolarisation of the membrane potential; this depolarisation results in opening of voltagedependent calcium channels, which leads to elevation of intracellular calcium levels and ultimately stimulates insulin secretion [32,33]. Although thiazolidinediones have been shown to stimulate insulin secretion in insulin-secreting cells [13,14], the pathway leading to closure of K ATP channels is not clear.…”

Section: Discussionmentioning

confidence: 99%

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

et al. 2009

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Aims/hypothesis Rosiglitazone, an insulin sensitiser, not only improves insulin sensitivity but also enhances insulin secretory capacity by ameliorating gluco-and lipotoxicity in beta cells. Rosiglitazone can stimulate insulin secretion at basal and high glucose levels via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. We hypothesised that regulation of phosphorylation of the ATP-sensitive potassium (K ATP ) channel might serve as a key step in the regulation of insulin secretion. Methods Insulin secretory responses were studied in an isolated pancreas perfusion system, cultured rat islets and MIN6 and RINm5F beta cells. Signal transduction pathways downstream of PI3K were explored to link rosiglitazone to K ATP channel conductance with patch clamp techniques and insulin secretion measured by ELISA. Results Rosiglitazone stimulated AMP-activated protein kinase (AMPK) activity and induced inhibition of the K ATP channel conductance in islet beta cells; both effects were blocked by the PI3K inhibitor LY294002. Following stimulation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a pharmacological activator, both AICAR-stimulated insulin secretion and inhibition of K ATP channel conductance were unaffected by LY294002, indicating that AMPK activation occurs at a site downstream of PI3K activity. The serine residue at amino acid position 385 of Kir6.2 was found to be the substrate phosphorylation site of AMPK when activated by rosiglitazone or AICAR. Conclusions/interpretation Our data indicate that PI3K-dependent activation of AMPK is required for rosiglitazonestimulated insulin secretion in pancreatic beta cells. Phosphorylation of the Ser 385 residue of the Kir6.2 subunit of the K ATP channel by AMPK may play a role in insulin secretion.

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Section: Discussionmentioning

confidence: 99%

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

et al. 2009

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“…It is possible that denatonium interacts with the sulfonylurea receptor that is an essential component of the functional KATP channel (29,30). Denatonium has some structural similarity to nateglinide, meglitinide, and other recently introduced blood glucose-lowering compounds that also act on the KATP channel and that displace glybenclamide from its binding site on SUR (27,(31)(32)(33)(34). However, denatonium did not displace glybenclamide from its binding site on the SUR.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Insulin Secretion by Denatonium, One of the Most Bitter-Tasting Substances Known

et al. 2003

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Denatonium, one of the most bitter-tasting substances known, stimulated insulin secretion in clonal HIT-T15 ␤-cells and rat pancreatic islets. Stimulation of release began promptly after exposure of the ␤-cells to denatonium, reached peak rates after 4 -5 min, and then declined to near basal values after 20 -30 min. In islets, no effect was observed at 2.8 mmol/l glucose, whereas a marked stimulation was observed at 8. M ultiple signal transduction mechanisms in taste cells detect sweet, sour, bitter, salty, and umami tastes and involve both receptormediated second messenger pathways and direct interactions with ion channels (1-3). Four mechanisms have been identified for signal transduction by bitter compounds. Two mechanisms result from bitter substances interacting with receptors of the T2R/TRB family and activation of gustducin (4 -10). In one, the ␣-subunit of gustducin activates cyclic nucleotide phosphodiesterase activity to decrease cyclic nucleotide monophosphate (cyclic NMP) levels and de-inhibit the activity of a cyclic NMP-inhibited cation channel leading to depolarization and increased [Ca 2ϩ ] i (11,12). In the second, the ␤␥-subunits of gustducin (probably ␤1␥13 and/or ␤3␥13) activate PLC␤2 and increase IP 3 and DAG levels (13,14). IP 3 increases [Ca 2ϩ ] i via IP 3 R3 activation (14 -16). A third mechanism involves a direct interaction and inhibition of K ϩ channels resulting in depolarization and increased [Ca 2ϩ ] i (17). The fourth known mechanism is the direct gating of nonselective cation channels and depolarization, again leading to increased [Ca 2ϩ ] i (18 -20). In all cases, increased [Ca 2ϩ ] i leads to increased neurotransmitter release and activation of the afferent gustatory nerves that transmit the bitter signal to the brain. There is evidence for the activation of multiple second messenger pathways in individual taste cells (4). There is also evidence that some bitter stimuli activate only subpopulations of bitter-sensitive taste cells (4 -6). Also, individual taste cells can respond selectively to different bitter substances (7). However, there is still much that is unknown about individual taste cell regulation.Stimulation of taste cell membranes with denatonium activates not only gustducin but also transducin (9), with which it shares high sequence homology (21). Because transducin mRNA is reported to be present in pancreatic islets at approximately one-fifth the level of that in the retina (22), we were interested to determine the effects of denatonium on insulin secretion in ␤-cells as a tool to study the potential involvement of gustducin or transducin in stimulus-secretion coupling. The experiments described here were performed on clonal HIT-T15 cells and rat pancreatic islets. RESEARCH DESIGN AND METHODSCell culture. Clonal HIT-T15 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 100 g/ml streptomycin, and 100 units/ml penicillin in an atmosphere of 95% air and 5% CO 2 . Cells of passage numbers 72-85 were used for the expe...

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“…in 81). More recent work has made it clear that the sulfonylurea group is not essential for hypoglycemic activity, but rather provides a properly positioned anionic group (78,79). The importance of this work is being rediscovered, and structure-function studies on SUR1 and SUR2 have begun to provide structural information about the nature of the "A" and "B" sites (rev.…”

Section: Sur1 Has a Multifaceted Binding Pocketmentioning

confidence: 99%

Toward Linking Structure With Function in ATP-Sensitive K+ Channels

et al. 2004

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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 (K ATP channels) (K IR 6.0/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 NH 2 -terminal bundle of five ␣-helices found in SURs, binds to and activates K IR 6.0. The adjacent cytoplasmic L0 linker serves a dual function, acting as a tether to link the MDR-like core to the K IR 6.2/TMD0 complex and exerting bidirectional control over channel gating via interactions with the NH 2 -terminus of the K IR . 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 COOHterminal 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 K IR NH 2 -terminus. Diabetes 53 (Suppl. 3):S104 -S112, 2004 T he regulation of insulin secretion from pancreatic ␤-cells in the islets of Langerhans is under the orchestration of multiple conductors. While glucose metabolism and changes in cellular energy status ultimately drive insulin output, a variety of inputs converge to modify the rate of secretion and thus maintain blood glucose levels within normal limits. Understanding the molecular basis of these inputs provides multiple routes for therapeutic intervention to both augment and diminish insulin secretion in disorders of glucose homeostasis. The ionic pathway, particularly ATPsensitive K ϩ channels (K ATP channels), has been an effective target, based on the observations by Janbon and colleagues that treatment with a sulfonamide, 2254 RP, produced severe hypoglycemia, as well as subsequent studies by Loubatiè res that the RP compound stimulated insulin release (rev. in 1-3). In pancreatic ␤-cells, K ATP channels are part of the ionic triggering mechanism that increases insulin secretion in response to increased glucose metabolism. The activity of K ATP channels is modulated by changes in the ATP/ADP ratio. In the absence of nucleotides, these channels are spontaneously active, but binding of ATP to the K IR subunits (the half-maximal inhibitory concentration [IC 50 ] for ATP is ϳ10 mol/l) inhibits activity. This inhibition can be antagonized by MgADP acting through the sulfonylurea receptor (SUR). The coupling of membrane potential with cellular metabolism provides a means to adjust the activity of voltagegated Ca 2ϩ channels and, thus, modulate Ca 2ϩ -dependent insulin exocytosis. K ATP channels are known targets for hypoglycemic sulfonylureas like tolbutamide and glibenclamide and for nonsulfonylureas like nateglinide and repaglinide, which increase insulin ...

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Structural requirements of sulphonylureas and analogues for interaction with sulphonylurea receptor subtypes

Cited by 41 publications

References 36 publications

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

Stimulation of Insulin Secretion by Denatonium, One of the Most Bitter-Tasting Substances Known

Toward Linking Structure With Function in ATP-Sensitive K+ Channels

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