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Show Ling Shyng - One of the best experts on this subject based on the ideXlab platform.
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functional characterization of activating mutations in the Sulfonylurea Receptor 1 abcc8 causing neonatal diabetes mellitus in asian indian children
Pediatric Diabetes, 2019Co-Authors: Venkatesan Radha, Viswanathan Mohan, Kandasamy Balamurugan, Babu Kavitha, Zhongying Yang, Show Ling ShyngAbstract:BACKGROUND: Gain-of-function of ATP-sensitive K+ (KATP ) channels because of mutations in the genes encoding SUR1 (ABCC8) or Kir6.2 (KCNJ11) is a major cause of neonatal diabetes mellitus (NDM). Our aim is to determine molecular defects in KATP channels caused by ABCC8 mutations in Asian Indian children with NDM by in vitro functional studies. METHODS: Wild-type (WT; NM_000352.4) or mutant Sulfonylurea Receptor 1 (SUR1) and Kir6.2 were co-expressed in COSm6 cells. Biogenesis efficiency and surface expression of mutant channels were assessed by immunoblotting and immunostaining. The response of mutant channels to cytoplasmic ATP and ADP was assessed by inside-out patch-clamp recordings. The response of mutant channels to known KATP inhibitors in intact cells were determined by 86 Rb efflux assays. RESULTS: Five SUR1 missense mutations, D212Y, P254S, R653Q, R992C, and Q1224H, were studied and showed increased activity in MgATP/MgADP. Two of the mutants, D212Y and P254S, also showed reduced response to ATP4- inhibition, as well as markedly reduced surface expression. Moreover, all five mutants were inhibited by the KATP channel inhibitors glibenclamide and carbamazepine. CONCLUSIONS: The study shows the mechanisms by which five SUR1 mutations identified in Asian Indian NDM patients affect KATP channel function to cause the disease. The reduced ATP4- sensitivity caused by the D212Y and P254S mutations in the L0 of SUR1 provides novel insight into the role of L0 in channel inhibition by ATP. The results also explain why Sulfonylurea therapy is effective in two patients and inform how it should be effective for the other three patients.
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pharmacological correction of trafficking defects in atp sensitive potassium channels caused by Sulfonylurea Receptor 1 mutations
Journal of Biological Chemistry, 2016Co-Authors: Gregory M Martin, Charles A Stanley, Emily A Rex, Prasanna K Devaraneni, Jerod S Denton, Kara E Boodhansingh, Diva D Deleon, Show Ling ShyngAbstract:ATP-sensitive potassium (KATP) channels play a key role in mediating glucose-stimulated insulin secretion by coupling metabolic signals to β-cell membrane potential. Loss of KATP channel function due to mutations in ABCC8 or KCNJ11, genes encoding the Sulfonylurea Receptor 1 (SUR1) or the inwardly rectifying potassium channel Kir6.2, respectively, results in congenital hyperinsulinism. Many SUR1 mutations prevent trafficking of channel proteins from the endoplasmic reticulum to the cell surface. Channel inhibitors, including Sulfonylureas and carbamazepine, have been shown to correct channel trafficking defects. In the present study, we identified 13 novel SUR1 mutations that cause channel trafficking defects, the majority of which are amenable to pharmacological rescue by glibenclamide and carbamazepine. By contrast, none of the mutant channels were rescued by KATP channel openers. Cross-linking experiments showed that KATP channel inhibitors promoted interactions between the N terminus of Kir6.2 and SUR1, whereas channel openers did not, suggesting the inhibitors enhance intersubunit interactions to overcome channel biogenesis and trafficking defects. Functional studies of rescued mutant channels indicate that most mutants rescued to the cell surface exhibited WT-like sensitivity to ATP, MgADP, and diazoxide. In intact cells, recovery of channel function upon trafficking rescue by reversible Sulfonylureas or carbamazepine was facilitated by the KATP channel opener diazoxide. Our study expands the list of KATP channel trafficking mutations whose function can be recovered by pharmacological ligands and provides further insight into the structural mechanism by which channel inhibitors correct channel biogenesis and trafficking defects.
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atp activates atp sensitive potassium channels composed of mutant Sulfonylurea Receptor 1 and kir6 2 with diminished pip2 sensitivity
Channels, 2011Co-Authors: Emily B Pratt, Show Ling ShyngAbstract:ATP-sensitive potassium (KATP) channels are inhibited by ATP and activated by phosphatidylinositol 4,5-bisphosphate (PIP2). Both channel subunits Kir6.2 and Sulfonylurea Receptor 1 (SUR1) contribute to gating: while Kir6.2 interacts with ATP and PIP2, SUR1 enhances sensitivity to both ligands. Recently, we showed that a mutation, E128K, in the N-terminal transmembrane domain of SUR1 disrupts functional coupling between SUR1 and Kir6.2, leading to reduced ATP and PIP2 sensitivities resembling channels formed by Kir6.2 alone. We show here that when E128K SUR1 was co-expressed with Kir6.2 mutants known to disrupt PIP2 gating, the resulting channels were surprisingly stimulated rather than inhibited by ATP. To explain this paradoxical gating behavior, we propose a model in which the open state of doubly mutant channels is highly unstable; ATP binding induces a conformational change in ATP-unbound closed channels that is conducive to brief opening when ATP unbinds, giving rise to the appearance of ATP-induced ...
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A role of the Sulfonylurea Receptor 1 in endocytic trafficking of ATP-sensitive potassium channels.
Traffic (Copenhagen Denmark), 2011Co-Authors: Cathrin E. Bruederle, Show Ling ShyngAbstract:The ATP-sensitive potassium (KATP) channel consisting of Sulfonylurea Receptor 1 (SUR1) and inward-rectifier potassium channel 6.2 (Kir6.2) has a well-established role in insulin secretion. Mutations in either subunit can lead to disease due to aberrant channel gating, altered channel density at the cell surface or a combination of both. Endocytic trafficking of channels at the plasma membrane is one way to influence surface channel numbers. It has been previously reported that channel endocytosis is dependent on a tyrosine-based motif in Kir6.2, while SUR1 alone is unable to internalize. In this study, we followed endocytic trafficking of surface channels in real time by live-cell imaging of channel subunits tagged with an extracellular minimal α-bungarotoxin-binding peptide labeled with a fluorescent dye. We show that SUR1 undergoes endocytosis independent of Kir6.2. Moreover, mutations in the putative endocytosis motif of Kir6.2, Y330C, Y330A and F333I are unable to prevent channel endocytosis. These findings challenge the notion that Kir6.2 bears the sole endocytic signal for KATP channels and support a role of SUR1 in this trafficking process.
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atp modulates interaction of syntaxin 1a with Sulfonylurea Receptor 1 to regulate pancreatic β cell katp channels
Journal of Biological Chemistry, 2011Co-Authors: Youhou Kang, Nathan Chang, Tao Liang, Huanli Xie, Show Ling Shyng, Yi Zhang, Yuk Man Leung, Joseph Chan, Robert G Tsushima, Herbert Y. GaisanoAbstract:ATP-sensitive potassium (KATP) channels are regulated by a variety of cytosolic factors (adenine nucleotides, Mg2+, phospholipids, and pH). We previously reported that KATP channels are also regulated by endogenous membrane-bound SNARE protein syntaxin-1A (Syn-1A), which binds both nucleotide-binding folds of Sulfonylurea Receptor (SUR)1 and 2A, causing inhibition of KATP channel activity in pancreatic islet β-cells and cardiac myocytes, respectively. In this study, we show that ATP dose-dependently inhibits Syn-1A binding to SUR1 at physiological concentrations, with the addition of Mg2+ causing a decrease in the ATP-induced inhibitory effect. This ATP disruption of Syn-1A binding to SUR1 was confirmed by FRET analysis in living HEK293 cells. Electrophysiological studies in pancreatic β-cells demonstrated that reduced ATP concentrations increased KATP channel sensitivity to Syn-1A inhibition. Depletion of endogenous Syn-1A in insulinoma cells by botulinum neurotoxin C1 proteolysis followed by rescue with exogenous Syn-1A showed that Syn-1A modulates KATP channel sensitivity to ATP. Thus, our data indicate that although both ATP and Syn-1A independently inhibit β-cell KATP channel gating, they could also influence the sensitivity of KATP channels to each other. These findings provide new insight into an alternate mechanism by which ATP regulates pancreatic β-cell KATP channel activity, not only by its direct actions on Kir6.2 pore subunit, but also via ATP modulation of Syn-1A binding to SUR1.
Marc J. Simard - One of the best experts on this subject based on the ideXlab platform.
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abcc8 Sulfonylurea Receptor 1 impact on brain atrophy after traumatic brain injury varies by sex
Journal of Neurotrauma, 2021Co-Authors: Swathi Tata, Volodymyr Gerzanich, Benjamin E. Zusman, Patrick M. Kochanek, Seung Kyoon Woo, Min Seong Kwon, Robert B Clark, Keri Janeskofeldman, Vincent Vagni, Marc J. SimardAbstract:Females have been understudied in pre-clinical and clinical traumatic brain injury (TBI), despite distinct biology and worse clinical outcomes versus males. Sulfonylurea Receptor 1 (SUR1) inhibitio...
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role of Sulfonylurea Receptor 1 and glibenclamide in traumatic brain injury a review of the evidence
International Journal of Molecular Sciences, 2020Co-Authors: Ruchira M. Jha, Josh Bell, Giuseppe Citerio, Claude J Hemphill, Taylor W Kimberly, Raj K Narayan, Juan Sahuquillo, Kevin N Sheth, Marc J. SimardAbstract:Cerebral edema and contusion expansion are major determinants of morbidity and mortality after TBI. Current treatment options are reactive, suboptimal and associated with significant side effects. First discovered in models of focal cerebral ischemia, there is increasing evidence that the Sulfonylurea Receptor 1 (SUR1)-Transient Receptor potential melastatin 4 (TRPM4) channel plays a key role in these critical secondary injury processes after TBI. Targeted SUR1-TRPM4 channel inhibition with glibenclamide has been shown to reduce edema and progression of hemorrhage, particularly in preclinical models of contusional TBI. Results from small clinical trials evaluating glibenclamide in TBI have been encouraging. A Phase-2 study evaluating the safety and efficacy of intravenous glibenclamide (BIIB093) in brain contusion is actively enrolling subjects. In this comprehensive narrative review, we summarize the molecular basis of SUR1-TRPM4 related pathology and discuss TBI-specific expression patterns, biomarker potential, genetic variation, preclinical experiments, and clinical studies evaluating the utility of treatment with glibenclamide in this disease.
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sur1 trpm4 promising target for brain edema treatment in brain edema from molecular mechanisms to clinical practice
Brain Edema#R##N#From Molecular Mechanisms to Clinical Practice, 2017Co-Authors: Sebastian Urday, Kevin N Sheth, Marc J. SimardAbstract:Brain edema after acute neurological injury causes significant morbidity and mortality. In this chapter, we highlight the critical role of the Sulfonylurea Receptor 1–transient Receptor potential M4 (SUR1–TRPM4) channel in the pathogenesis of brain edema across various neurocritical care conditions. We emphasize that SUR1–TRPM4 activation is pivotal at every stage in edema formation. It contributes to every type of edema (cytotoxic, ionic, and vasogenic) and to total microvascular failure, which results in the extravasation of blood and the formation of petechial hemorrhages. We present examples from experimental models that demonstrate that selective blockade of SUR1–TRPM4 with glibenclamide results in improvement in edema, lesion volume, mortality, and neurological function. Clinical studies supporting the role of SUR1–TRPM4 in edema formation in humans are also presented. Although definitive phase III studies are needed, the ability to block SUR1–TRPM4 over a broad time window with a safe medication (glibenclamide) is emerging as a highly promising approach to treat brain edema.
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Review Glibenclamide for the Treatment of Ischemic and Hemorrhagic Stroke
2016Co-Authors: Nicholas Caffes, Volodymyr Gerzanich, David B. Kurl, Marc J. SimardAbstract:Abstract: Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial Sulfonylurea Receptor 1–transient Receptor potential melastatin 4 (Sur1–Trpm4) channels and, in some cases, microglial KATP (Sur1–Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other Sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on Sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory an
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ORIGINAL ARTICLE Sulfonylurea Receptor 1 Expression in Human Cerebral Infarcts
2016Co-Authors: Marc J. SimardAbstract:In animal models of stroke, Sulfonylurea Receptor 1 (Sur1), a member of the adenosine triphosphate binding cassette transporter gene family, is transcriptionally upregulated in neural and vascular cells in which it plays a leading role in edema formation and necrotic cell death. To date, expression of Sur1 in the brains of humans with cerebral infarcts has not been systematically evaluated. We examined Sur1 expression in postmortem specimens obtained from 13 patients within the first 31 days after focal infarcts, 5 patients with lacunar infarcts, and 6 normal control brains using immunohistochemistry. Elevated immunoreactivity for Sur1 was detected in all cases of focal infarcts, with 3 distinct temporal patterns of expression: 1) neurons and endothelium showed the greatest elevation during the first week, after which levels declined; 2) astrocytes and microglia/macrophages showed progressive increases during the first 31 days; and 3) neu-trophils near the infarct showed prominent immunoreactivity that did not change over time. Upregulation of Sur1 was corroborated using in situ hybridization for Abcc8 mRNA. Sulfonylurea Receptor 1 im-munoreactivity in lacunar infarcts was less prominent and more sporadic than in nonlacunar infarcts. In conjunction with previous studies, these data suggest that Sur1 may be a promising treatment target in patients with acute cerebral infarction
Volodymyr Gerzanich - One of the best experts on this subject based on the ideXlab platform.
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abcc8 Sulfonylurea Receptor 1 impact on brain atrophy after traumatic brain injury varies by sex
Journal of Neurotrauma, 2021Co-Authors: Swathi Tata, Volodymyr Gerzanich, Benjamin E. Zusman, Patrick M. Kochanek, Seung Kyoon Woo, Min Seong Kwon, Robert B Clark, Keri Janeskofeldman, Vincent Vagni, Marc J. SimardAbstract:Females have been understudied in pre-clinical and clinical traumatic brain injury (TBI), despite distinct biology and worse clinical outcomes versus males. Sulfonylurea Receptor 1 (SUR1) inhibitio...
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Review Glibenclamide for the Treatment of Ischemic and Hemorrhagic Stroke
2016Co-Authors: Nicholas Caffes, Volodymyr Gerzanich, David B. Kurl, Marc J. SimardAbstract:Abstract: Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial Sulfonylurea Receptor 1–transient Receptor potential melastatin 4 (Sur1–Trpm4) channels and, in some cases, microglial KATP (Sur1–Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other Sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on Sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory an
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inhibition of the sur1 trpm4 channel reduces neuroinflammation and cognitive impairment in subarachnoid hemorrhage
Stroke, 2013Co-Authors: Cigdem Tosun, Rupal I. Mehta, Rudy J. Castellani, Volodymyr Gerzanich, Seung Kyoon Woo, Min Seong Kwon, David B Kurland, Joyce L Dejong, Marc J. SimardAbstract:Background and Purpose—Subarachnoid hemorrhage (SAH) can leave patients with memory impairments that may not recover fully. Molecular mechanisms are poorly understood, and no treatment is available. The Sulfonylurea Receptor 1–transient Receptor potential melastatin 4 (Sur1-Trpm4) channel plays an important role in acute central nervous system injury. We evaluated upregulation of Sur1-Trpm4 in humans with SAH and, in rat models of SAH, we examined Sur1-Trpm4 upregulation, its role in barrier dysfunction and neuroinflammation, and its consequences on spatial learning. Methods—We used Forster resonance energy transfer to detect coassociated Sur1 and Trpm4 in human autopsy brains with SAH. We studied rat models of SAH involving filament puncture of the internal carotid artery or injection of blood into the subarachnoid space of the entorhinal cortex. In rats, we used Forster resonance energy transfer and coimmunoprecipitation to detect coassociated Sur1 and Trpm4, we measured immunoglobulin G extravasation a...
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the Sulfonylurea Receptor 1 sur1 transient Receptor potential melastatin 4 trpm4 channel
Journal of Biological Chemistry, 2013Co-Authors: Seung Kyoon Woo, Volodymyr Gerzanich, Min Seong Kwon, A V Ivanov, Marc J. SimardAbstract:Abstract The Sulfonylurea Receptor 1 (Sur1)-NCCa-ATP channel plays a central role in necrotic cell death in central nervous system (CNS) injury, including ischemic stroke, and traumatic brain and spinal cord injury. Here, we show that Sur1-NCCa-ATP channels are formed by co-assembly of Sur1 and transient Receptor potential melastatin 4 (Trpm4). Co-expression of Sur1 and Trpm4 yielded Sur1-Trpm4 heteromers, as shown in experiments with Forster resonance energy transfer (FRET) and co-immunoprecipitation. Co-expression of Sur1 and Trpm4 also yielded functional Sur1-Trpm4 channels with biophysical properties of Trpm4 and pharmacological properties of Sur1. Co-assembly with Sur1 doubled the affinity of Trpm4 for calmodulin and doubled its sensitivity to intracellular calcium. Experiments with FRET and co-immunoprecipitation showed de novo appearance of Sur1-Trpm4 heteromers after spinal cord injury in rats. Our findings depart from the long-held view of an exclusive association between Sur1 and KATP channels and reveal an unexpected molecular partnership with far-ranging implications for CNS injury.
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the Sulfonylurea Receptor 1 sur1 transient Receptor potential melastatin 4 trpm4 channel
Journal of Biological Chemistry, 2013Co-Authors: Seung Kyoon Woo, Volodymyr Gerzanich, Min Seong Kwon, Alexander Ivanov, Marc J. SimardAbstract:The Sulfonylurea Receptor 1 (Sur1)-NCCa-ATP channel plays a central role in necrotic cell death in central nervous system (CNS) injury, including ischemic stroke, and traumatic brain and spinal cord injury. Here, we show that Sur1-NCCa-ATP channels are formed by co-assembly of Sur1 and transient Receptor potential melastatin 4 (Trpm4). Co-expression of Sur1 and Trpm4 yielded Sur1-Trpm4 heteromers, as shown in experiments with Forster resonance energy transfer (FRET) and co-immunoprecipitation. Co-expression of Sur1 and Trpm4 also yielded functional Sur1-Trpm4 channels with biophysical properties of Trpm4 and pharmacological properties of Sur1. Co-assembly with Sur1 doubled the affinity of Trpm4 for calmodulin and doubled its sensitivity to intracellular calcium. Experiments with FRET and co-immunoprecipitation showed de novo appearance of Sur1-Trpm4 heteromers after spinal cord injury in rats. Our findings depart from the long-held view of an exclusive association between Sur1 and KATP channels and reveal an unexpected molecular partnership with far-ranging implications for CNS injury. Background: Sur1-NCCa-ATP channels implicated in acute CNS injury are hypothesized to be formed by co-association of Sur1 and a nonselective cation channel. Results: Sur1 and Trpm4 form heteromers that exhibit pharmacological properties of Sur1 and biophysical properties of Trpm4. Conclusion: Sur1 and Trpm4 co-assemble to form the unique Sur1-Trpm4 channel. Significance: Identification of Sur1-Trpm4 channels has broad implications in acute CNS injuries.
Bernard Pirotte - One of the best experts on this subject based on the ideXlab platform.
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Hydroxylated Analogues of ATP-Sensitive Potassium Channel Openers Belonging to the Group of 6- and/or 7-Substituted 3-Isopropylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides: Toward an Improvement in Sulfonylurea Receptor 1 Selectivity and Metabolism S
2016Co-Authors: Pascal De Tullio, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, F Somers, Patrice Chiap, Bernard PirotteAbstract:Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic tissue (compared to vascular smooth muscle tissue), leading to compounds with an improved Sulfonylurea Receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a
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hydroxylated analogues of atp sensitive potassium channel openers belonging to the group of 6 and or 7 substituted 3 isopropylamino 4h 1 2 4 benzothiadiazine 1 1 dioxides toward an improvement in Sulfonylurea Receptor 1 selectivity and metabolism sta
Journal of Medicinal Chemistry, 2011Co-Authors: Pascal De Tullio, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, F Somers, Patrice Chiap, Bernard PirotteAbstract:Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic tissue (compared to vascular smooth muscle tissue), leading to compounds with an improved Sulfonylurea Receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a.
Sian Ellard - One of the best experts on this subject based on the ideXlab platform.
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mutations of the same conserved glutamate residue in nbd2 of the Sulfonylurea Receptor 1 subunit of the katp channel can result in either hyperinsulinism or neonatal diabetes
Diabetes, 2011Co-Authors: Roope Mannikko, Sarah E Flanagan, Sian Ellard, Andrew T Hattersley, Xiuli Sim, David G Segal, Khalid Hussain, Frances M. AshcroftAbstract:OBJECTIVE Two novel mutations (E1506D, E1506G) in the nucleotide-binding domain 2 (NBD2) of the ATP-sensitive K+ channel (KATP channel) Sulfonylurea Receptor 1 (SUR1) subunit were detected heterozygously in patients with neonatal diabetes. A mutation at the same residue (E1506K) was previously shown to cause congenital hyperinsulinemia. We sought to understand why mutations at the same residue can cause either neonatal diabetes or hyperinsulinemia. RESEARCH DESIGN AND METHODS Neonatal diabetic patients were sequenced for mutations in ABCC8 (SUR1) and KCNJ11 (Kir6.2). Wild-type and mutant KATP channels were expressed in Xenopuslaevis oocytes and studied with electrophysiological methods. RESULTS Oocytes expressing neonatal diabetes mutant channels had larger resting whole-cell KATP currents than wild-type, consistent with the patients’ diabetes. Conversely, no E1506K currents were recorded at rest or after metabolic inhibition, as expected for a mutation causing hyperinsulinemia. KATP channels are activated by Mg-nucleotides (via SUR1) and blocked by ATP (via Kir6.2). All mutations decreased channel activation by MgADP but had little effect on MgATP activation, as assessed using an ATP-insensitive Kir6.2 subunit. Importantly, using wild-type Kir6.2, a 30-s preconditioning exposure to physiological MgATP concentrations (>300 µmol/L) caused a marked reduction in the ATP sensitivity of neonatal diabetic channels, a small decrease in that of wild-type channels, and no change for E1506K channels. This difference in MgATP inhibition may explain the difference in resting whole-cell currents found for the neonatal diabetes and hyperinsulinemia mutations. CONCLUSIONS Mutations in the same residue can cause either hyperinsulinemia or neonatal diabetes. Differentially altered nucleotide regulation by NBD2 of SUR1 can explain the respective clinical phenotypes.
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update of mutations in the genes encoding the pancreatic beta cell k atp channel subunits kir6 2 kcnj11 and Sulfonylurea Receptor 1 abcc8 in diabetes mellitus and hyperinsulinism
Human Mutation, 2009Co-Authors: Sarah E Flanagan, Severine Clauin, Christine Bellannechantelot, Pascale De Lonlay, Lorna W Harries, Anna L Gloyn, Sian EllardAbstract:The beta-cell ATP-sensitive potassium (KATP) channel is a key component of stimulus-secretion coupling in the pancreatic beta-cell. The channel couples metabolism to membrane electrical events bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis it is therefore not surprising that mutations in the genes encoding for the two essential subunits of the channel can result in both hypo- and hyperglycemia. The channel consists of four subunits of the inwardly rectifying potassium channel Kir6.2 and four subunits of the Sulfonylurea Receptor 1 (SUR1). It has been known for some time that loss of function mutations in KCNJ11, which encodes for Kir6.2, and ABCC8, which encodes for SUR1, can cause oversecretion of insulin and result in hyperinsulinism of infancy, while activating mutations in KCNJ11 and ABCC8 have recently been described that result in the opposite phenotype of diabetes. This review focuses on reported mutations in both genes, the spectrum of phenotypes, and the implications for treatment on diagnosing patients with mutations in these genes. Hum Mutat 0, 1–12, 2008. © 2008 Wiley-Liss, Inc.
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update of mutations in the genes encoding the pancreatic beta cell k atp channel subunits kir6 2 kcnj11 and Sulfonylurea Receptor 1 abcc8 in diabetes mellitus and hyperinsulinism
Human Mutation, 2009Co-Authors: Sarah E Flanagan, Severine Clauin, Christine Bellannechantelot, Pascale De Lonlay, Lorna W Harries, Anna L Gloyn, Sian EllardAbstract:The beta-cell ATP-sensitive potassium (K(ATP)) channel is a key component of stimulus-secretion coupling in the pancreatic beta-cell. The channel couples metabolism to membrane electrical events bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis it is therefore not surprising that mutations in the genes encoding for the two essential subunits of the channel can result in both hypo- and hyperglycemia. The channel consists of four subunits of the inwardly rectifying potassium channel Kir6.2 and four subunits of the Sulfonylurea Receptor 1 (SUR1). It has been known for some time that loss of function mutations in KCNJ11, which encodes for Kir6.2, and ABCC8, which encodes for SUR1, can cause oversecretion of insulin and result in hyperinsulinism of infancy, while activating mutations in KCNJ11 and ABCC8 have recently been described that result in the opposite phenotype of diabetes. This review focuses on reported mutations in both genes, the spectrum of phenotypes, and the implications for treatment on diagnosing patients with mutations in these genes.
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effective treatment with oral Sulfonylureas in patients with diabetes due to Sulfonylurea Receptor 1 sur1 mutations
Diabetes Care, 2008Co-Authors: Meena Rafiq, Sarah E Flanagan, Annmarie Patch, Beverley M Shields, Sian Ellard, Andrew T HattersleyAbstract:OBJECTIVE — Neonatal diabetes can result from mutations in the Kir6.2 or Sulfonylurea Receptor 1 (SUR1) subunits of the ATP-sensitive K channel. Transfer from insulin to oral Sulfonylureas in patients with neonatal diabetes due to Kir6.2 mutations is well described, but less is known about changing therapy in patients with SUR1 mutations. We aimed to describe the response to Sulfonylurea therapy in patients with SUR1 mutations and to compare it with Kir6.2 mutations. RESEARCH DESIGN AND METHODS — We followed 27 patients with SUR1 mutations for at least 2 months after attempted transfer to Sulfonylureas. Information was collected on clinical features, treatment before and after transfer, and the transfer protocol used. We compared successful and unsuccessful transfer patients, glycemic control before and after transfer, and treatment requirements in patients with SUR1 and Kir6.2 mutations. RESULTS — Twenty-three patients (85%) successfully transferred onto Sulfonylureas without significant side effects or increased hypoglycemia and did not need insulin injections. In these patients, median A1C fell from 7.2% (interquartile range 6.6 – 8.2%) on insulin to 5.5% (5.3– 6.2%) on Sulfonylureas (P 0.01). When compared with Kir6.2 patients, SUR1 patients
