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Marc J. Simard - One of the best experts on this subject based on the ideXlab platform.
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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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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
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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.
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Sulfonylurea Receptor 1 in central nervous system injury a focused review
Journal of Cerebral Blood Flow and Metabolism, 2012Co-Authors: Marc J. Simard, Kyoon S Woo, Gary Schwartzbauer, Volodymyr GerzanichAbstract:The Sulfonylurea Receptor 1 (Sur1)-regulated NCCa-ATP channel is a nonselective cation channel that is regulated by intracellular calcium and adenosine triphosphate. The channel is not constitutively expressed, but is transcriptionally upregulated de novo in all cells of the neurovascular unit, in many forms of central nervous system (CNS) injury, including cerebral ischemia, traumatic brain injury (TBI), spinal cord injury (SCI), and subarachnoid hemorrhage (SAH). The channel is linked to microvascular dysfunction that manifests as edema formation and delayed secondary hemorrhage. Also implicated in oncotic cell swelling and oncotic (necrotic) cell death, the channel is a major molecular mechanism of ‘accidental necrotic cell death' in the CNS. In animal models of SCI, pharmacological inhibition of Sur1 by glibenclamide, as well as gene suppression of Abcc8, prevents delayed capillary fragmentation and tissue necrosis. In models of stroke and TBI, glibenclamide ameliorates edema, secondary hemorrhage, and tissue damage. In a model of SAH, glibenclamide attenuates the inflammatory response due to extravasated blood. Clinical trials of an intravenous formulation of glibenclamide in TBI and stroke underscore the importance of recent advances in understanding the role of the Sur1-regulated NCCa-ATP channel in acute ischemic, traumatic, and inflammatory injury to the CNS.
Volodymyr Gerzanich - One of the best experts on this subject based on the ideXlab platform.
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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.
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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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Sulfonylurea Receptor 1 expression in human cerebral infarcts.
Journal of neuropathology and experimental neurology, 2013Co-Authors: Rupal I. Mehta, Svetlana Ivanova, Cigdem Tosun, Rudy J. Castellani, Volodymyr Gerzanich, J. Marc 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) neutrophils 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 immunoreactivity 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.
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The Sulfonylurea Receptor 1 (Sur1)-Transient Receptor Potential Melastatin 4 (Trpm4) Channel *
The Journal of biological chemistry, 2012Co-Authors: Seung Kyoon Woo, Volodymyr Gerzanich, Min Seong Kwon, Alexander R. Ivanov, J. Marc 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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Sulfonylurea Receptor 1 in central nervous system injury a focused review
Journal of Cerebral Blood Flow and Metabolism, 2012Co-Authors: Marc J. Simard, Kyoon S Woo, Gary Schwartzbauer, Volodymyr GerzanichAbstract:The Sulfonylurea Receptor 1 (Sur1)-regulated NCCa-ATP channel is a nonselective cation channel that is regulated by intracellular calcium and adenosine triphosphate. The channel is not constitutively expressed, but is transcriptionally upregulated de novo in all cells of the neurovascular unit, in many forms of central nervous system (CNS) injury, including cerebral ischemia, traumatic brain injury (TBI), spinal cord injury (SCI), and subarachnoid hemorrhage (SAH). The channel is linked to microvascular dysfunction that manifests as edema formation and delayed secondary hemorrhage. Also implicated in oncotic cell swelling and oncotic (necrotic) cell death, the channel is a major molecular mechanism of ‘accidental necrotic cell death' in the CNS. In animal models of SCI, pharmacological inhibition of Sur1 by glibenclamide, as well as gene suppression of Abcc8, prevents delayed capillary fragmentation and tissue necrosis. In models of stroke and TBI, glibenclamide ameliorates edema, secondary hemorrhage, and tissue damage. In a model of SAH, glibenclamide attenuates the inflammatory response due to extravasated blood. Clinical trials of an intravenous formulation of glibenclamide in TBI and stroke underscore the importance of recent advances in understanding the role of the Sur1-regulated NCCa-ATP channel in acute ischemic, traumatic, and inflammatory injury to the CNS.
Colin G Nichols - One of the best experts on this subject based on the ideXlab platform.
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on potential interactions between non selective cation channel trpm4 and Sulfonylurea Receptor sur1
Journal of Biological Chemistry, 2012Co-Authors: Monica Salarabanal, Shizhen Wang, Colin G NicholsAbstract:The Sulfonylurea Receptor SUR1 associates with Kir6.2 or Kir6.1 to form K(ATP) channels, which link metabolism to excitability in multiple cell types. The strong physical coupling of SUR1 with Kir6 subunits appears exclusive, but recent studies argue that SUR1 also modulates TRPM4, a member of the transient Receptor potential family of non-selective cation channels. It has been reported that, following stroke, brain, or spinal cord injury, SUR1 is increased in neurovascular cells at the site of injury. This is accompanied by up-regulation of a non-selective cation conductance with TRPM4-like properties and apparently sensitive to Sulfonylureas, leading to the postulation that post-traumatic non-selective cation currents are determined by TRPM4/SUR1 channels. To investigate the mechanistic hypothesis for the coupling between TRPM4 and SUR1, we performed electrophysiological and FRET studies in COSm6 cells expressing TRPM4 channels with or without SUR1. TRPM4-mediated currents were Ca(2+)-activated, voltage-dependent, underwent desensitization, and were inhibited by ATP but were insensitive to glibenclamide and tolbutamide. These properties were not affected by cotransfection with SUR1. When the same SUR1 was cotransfected with Kir6.2, functional K(ATP) channels were formed. In cells cotransfected with Kir6.2, SUR1, and TRPM4, we measured K(ATP)-mediated K(+) currents and Ca(2+)-activated, Sulfonylurea-insensitive Na(+) currents in the same patch, further showing that SUR1 controls K(ATP) channel activity but not TRPM4 channels. FRET signal between fluorophore-tagged TRPM4 subunits was similar to that between Kir6.2 and SUR1, whereas there was no detectable FRET efficiency between TRPM4 and SUR1. Our data suggest that functional or structural association of TRPM4 and SUR1 is unlikely.
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Sulfonylurea Receptor 1 subunits of atp sensitive potassium channels and myocardial ischemia reperfusion injury
Trends in Cardiovascular Medicine, 2009Co-Authors: David J. Lefer, Colin G Nichols, William A. CoetzeeAbstract:K ATP channels are generally cardioprotective under conditions of metabolic impairment, consisting of pore-forming (Kir6.1 and/or Kir6.2) and sulphonylurea-binding, modulatory subunits [Sulfonylurea Receptor (SUR) 1, 2A, or 2B]. Cardiovascular K ATP channels are generally thought to consist of Kir6.2/SUR2A subunits (in the case of heart muscle) or Kir6.1/SUR2B subunits (smooth muscle), whereas SUR1-containing channels have well-documented roles in pancreatic insulin release. Recent data, however, demonstrated the presence of SUR1 subunits in mouse cardiac tissue (particularly in atria) and a surprising protection from myocardial ischemia/reperfusion in SUR1-null mice. Here, we review some of the extra-pancreatic roles assigned to SUR1 subunits and consider whether these might be involved in the sequelae of ischemia/reperfusion.
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Sulfonylurea Receptor 1 subunits of ATP-sensitive potassium channels and myocardial ischemia/reperfusion injury.
Trends in cardiovascular medicine, 2009Co-Authors: David J. Lefer, Colin G Nichols, William A. CoetzeeAbstract:K ATP channels are generally cardioprotective under conditions of metabolic impairment, consisting of pore-forming (Kir6.1 and/or Kir6.2) and sulphonylurea-binding, modulatory subunits [Sulfonylurea Receptor (SUR) 1, 2A, or 2B]. Cardiovascular K ATP channels are generally thought to consist of Kir6.2/SUR2A subunits (in the case of heart muscle) or Kir6.1/SUR2B subunits (smooth muscle), whereas SUR1-containing channels have well-documented roles in pancreatic insulin release. Recent data, however, demonstrated the presence of SUR1 subunits in mouse cardiac tissue (particularly in atria) and a surprising protection from myocardial ischemia/reperfusion in SUR1-null mice. Here, we review some of the extra-pancreatic roles assigned to SUR1 subunits and consider whether these might be involved in the sequelae of ischemia/reperfusion.
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Functional clustering of mutations in the dimer interface of the nucleotide binding folds of the Sulfonylurea Receptor.
The Journal of biological chemistry, 2008Co-Authors: Ricard Masia, Colin G NicholsAbstract:ATP-sensitive K+ (KATP) channels modulate their activity as a function of inhibitory ATP and stimulatory Mg-nucleotides. They are constituted by two proteins: a pore-forming K+ channel subunit (Kir6.1, Kir6.2) and a regulatory Sulfonylurea Receptor (SUR) subunit, an ATP-binding cassette (ABC) transporter that confers MgADP stimulation to the channel. Channel regulation by MgADP is dependent on nucleotide interaction with the cytoplasmic nucleotide binding folds (NBF1 and NBF2) of the SUR subunit. Crystal structures of bacterial ABC proteins indicate that NBFs form as dimers, suggesting that NBF1-NBF2 heterodimers may form in SUR and other eukaryotic ABC proteins. We have modeled SUR1 NBF1 and NBF2 as a heterodimer, and tested the validity of the predicted dimer interface by systematic mutagenesis. Engineered cysteine mutations in this region have significant effects, both positive and negative, on MgADP stimulation of KATP channels in excised patches and on macroscopic channel activity in intact cells. Additionally, the mutations cluster in the model structure according to their functional effect, such that patterns of alteration emerge. Of note, three gain-of-function mutations, leading to MgADP hyperstimulation of the channel, are located in the D-loop region at the center of the predicted dimer interface. Overall, the data support the idea that SUR1 NBFs assemble as heterodimers and that this interaction is functionally critical.
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role of Sulfonylurea Receptor type 1 subunits of atp sensitive potassium channels in myocardial ischemia reperfusion injury
Circulation, 2008Co-Authors: John W. Elrod, Colin G Nichols, Maddison D. Harrell, Thomas P. Flagg, Susheel Gundewar, Mark A. Magnuson, William A. Coetzee, David J. LeferAbstract:Background— Opening of cardiac ATP-sensitive potassium channels (KATP channels) is a well-characterized protective mechanism against ischemia and reperfusion injury. Evidence exists for an involvement of both sarcolemmal and mitochondrial KATP channels in such protection. Classically, cardiac sarcolemmal KATP channels are thought to be composed of Kir6.2 (inward-rectifier potassium channel 6.2) and SUR2A (Sulfonylurea Receptor type 2A) subunits; however, the evidence is strong that SUR1 (Sulfonylurea Receptor type 1) subunits are also expressed in the heart and that they may have a functional role. The aim of this study, therefore, was to examine the role of SUR1 in myocardial infarction. Methods and Results— We subjected mice lacking SUR1 subunits to in vivo myocardial ischemia/reperfusion injury. Interestingly, the SUR1-null mice were markedly protected against the ischemic insult, displaying a reduced infarct size and preservation of left ventricular function, which suggests a role for this KATP channe...
Show Ling Shyng - One of the best experts on this subject based on the ideXlab platform.
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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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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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neonatal diabetes caused by mutations in Sulfonylurea Receptor 1 interplay between expression and mg nucleotide gating defects of atp sensitive potassium channels
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Qing Zhou, Intza Garin, Luis Castano, Jesus Argente, Ma Teresa Munozcalvo, Guiomar Perez De Nanclares, Show Ling ShyngAbstract:Context: ATP-sensitive potassium (KATP) channels regulate insulin secretion by coupling glucose metabolism to β-cell membrane potential. Gain-of-function mutations in the Sulfonylurea Receptor 1 (SUR1) or Kir6.2 channel subunit underlie neonatal diabetes. Objective: The objective of the study was to determine the mechanisms by which two SUR1 mutations, E208K and V324M, associated with transient neonatal diabetes affect KATP channel function. Design: E208K or V324M mutant SUR1 was coexpressed with Kir6.2 in COS cells, and expression and gating properties of the resulting channels were assessed biochemically and electrophysiologically. Results: Both E208K and V324M augment channel response to MgADP stimulation without altering sensitivity to ATP4− or Sulfonylureas. Surprisingly, whereas E208K causes only a small increase in MgADP response consistent with the mild transient diabetes phenotype, V324M causes a severe activating gating defect. Unlike E208K, V324M also impairs channel expression at the cell surf...
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Sulfonylurea Receptor 1 mutations that cause opposite insulin secretion defects with chemical chaperone exposure
Journal of Biological Chemistry, 2009Co-Authors: Emily B Pratt, Fei Fei Yan, Charles A Stanley, Show Ling ShyngAbstract:Abstract The β-cell ATP-sensitive potassium (KATP) channel composed of Sulfonylurea Receptor SUR1 and potassium channel Kir6.2 serves a key role in insulin secretion regulation by linking glucose metabolism to cell excitability. Mutations in SUR1 or Kir6.2 that decrease channel function are typically associated with congenital hyperinsulinism, whereas those that increase channel function are associated with neonatal diabetes. Here we report that two hyperinsulinism-associated SUR1 missense mutations, R74W and E128K, surprisingly reduce channel inhibition by intracellular ATP, a gating defect expected to yield the opposite disease phenotype neonatal diabetes. Under normal conditions, both mutant channels showed poor surface expression due to retention in the endoplasmic reticulum, accounting for the loss of channel function phenotype in the congenital hyperinsulinism patients. This trafficking defect, however, could be corrected by treating cells with the oral hypoglycemic drugs Sulfonylureas, which we have shown previously to act as small molecule chemical chaperones for KATP channels. The R74W and E128K mutants thus rescued to the cell surface paradoxically exhibited ATP sensitivity 6- and 12-fold lower than wild-type channels, respectively. Further analyses revealed a nucleotide-independent decrease in mutant channel intrinsic open probability, suggesting the mutations may reduce ATP sensitivity by causing functional uncoupling between SUR1 and Kir6.2. In insulin-secreting cells, rescue of both mutant channels to the cell surface led to hyperpolarized membrane potentials and reduced insulin secretion upon glucose stimulation. Our results show that Sulfonylureas, as chemical chaperones, can dictate manifestation of the two opposite insulin secretion defects by altering the expression levels of the disease mutants.
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Sulfonylureas Correct Trafficking Defects of ATP-sensitive Potassium Channels Caused by Mutations in the Sulfonylurea Receptor
The Journal of biological chemistry, 2004Co-Authors: Fei Fei Yan, Chia Wei Lin, Elizabeth Weisiger, Etienne A. Cartier, Grit Taschenberger, Show Ling ShyngAbstract:Abstract The pancreatic ATP-sensitive potassium (KATP) channel, a complex of four Sulfonylurea Receptor 1 (SUR1) and four potassium channel Kir6.2 subunits, regulates insulin secretion by linking metabolic changes to β-cell membrane potential. Sulfonylureas inhibit KATP channel activities by binding to SUR1 and are widely used to treat type II diabetes. We report here that Sulfonylureas also function as chemical chaperones to rescue KATP channel trafficking defects caused by two SUR1 mutations, A116P and V187D, identified in patients with congenital hyperinsulinism. Sulfonylureas markedly increased cell surface expression of the A116P and V187D mutants by stabilizing the mutant SUR1 proteins and promoting their maturation. By contrast, diazoxide, a potassium channel opener that also binds SUR1, had no effect on surface expression of either mutant. Importantly, both mutant channels rescued to the cell surface have normal ATP, MgADP, and diazoxide sensitivities, demonstrating that SUR1 harboring either the A116P or the V187D mutation is capable of associating with Kir6.2 to form functional KATP channels. Thus, Sulfonylureas may be used to treat congenital hyperinsulinism caused by certain KATP channel trafficking mutations.
J. Marc Simard - One of the best experts on this subject based on the ideXlab platform.
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Sulfonylurea Receptor 1 expression in human cerebral infarcts.
Journal of neuropathology and experimental neurology, 2013Co-Authors: Rupal I. Mehta, Svetlana Ivanova, Cigdem Tosun, Rudy J. Castellani, Volodymyr Gerzanich, J. Marc 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) neutrophils 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 immunoreactivity 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.
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The Sulfonylurea Receptor 1 (Sur1)-Transient Receptor Potential Melastatin 4 (Trpm4) Channel *
The Journal of biological chemistry, 2012Co-Authors: Seung Kyoon Woo, Volodymyr Gerzanich, Min Seong Kwon, Alexander R. Ivanov, J. Marc 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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Sulfonylurea Receptor 1 in the germinal matrix of premature infants.
Pediatric research, 2008Co-Authors: J. Marc Simard, Svetlana Ivanova, Rudolph J. Castellani, Michael T. Koltz, Volodymyr GerzanichAbstract:Germinal matrix (GM) hemorrhage (GMH) is a major cause of mortality and of life-long morbidity from cerebral palsy. GMH is typically preceded by hypoxic/ischemic events and is believed to arise from rupture of weakened veins in the GM. In the CNS, hypoxia/ischemia up-regulate Sulfonylurea Receptor 1 (SUR1)-regulated NCCa-ATP channels in microvascular endothelium, with channel activation by depletion of ATP being responsible for progressive secondary hemorrhage. We hypothesized that this channel might be up-regulated in the GM of preterm infants at risk for GMH. Here, we studied expression of the regulatory subunit of the channel, SUR1, and its transcriptional antecedent, hypoxia inducible factor 1 (HIF1), in postmortem tissues of premature infants who either were at risk for or who sustained GMH. We found regionally specific up-regulation of HIF1 and of SUR1 protein and mRNA in GM tissues, compared with remote cortical tissues. Up-regulation was prominent in most progenitor cells, whereas in veins, SUR1 was found predominantly in infants who had sustained GMH compared with those without hemorrhage. Our data suggest that the SUR1-regulated NCCa-ATP channel may be associated with GMH, and that pharmacological block of these channels could potentially reduce the incidence of this devastating complication of prematurity.
