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[PMID]:29416045
[Au] Autor:Basco D; Zhang Q; Salehi A; Tarasov A; Dolci W; Herrera P; Spiliotis I; Berney X; Tarussio D; Rorsman P; Thorens B
[Ad] Endereço:Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.
[Ti] Título:α-cell glucokinase suppresses glucose-regulated glucagon secretion.
[So] Source:Nat Commun;9(1):546, 2018 02 07.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Glucagon secretion by pancreatic α-cells is triggered by hypoglycemia and suppressed by high glucose levels; impaired suppression of glucagon secretion is a hallmark of both type 1 and type 2 diabetes. Here, we show that α-cell glucokinase (Gck) plays a role in the control of glucagon secretion. Using mice with α-cell-specific inactivation of Gck (αGckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of K channels in α-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels. αGckKO mice display hyperglucagonemia in the fed state, which is associated with increased hepatic gluconeogenic gene expression and hepatic glucose output capacity. In adult mice, fed hyperglucagonemia is further increased and glucose intolerance develops. Thus, glucokinase governs an α-cell metabolic pathway that suppresses secretion at or above normoglycemic levels; abnormal suppression of glucagon secretion deregulates hepatic glucose metabolism and, over time, induces a pre-diabetic phenotype.
[Mh] Termos MeSH primário: Células Secretoras de Glucagon/metabolismo
Glucagon/secreção
Glucoquinase/genética
Intolerância à Glucose/metabolismo
Glucose/metabolismo
Hipoglicemia/metabolismo
[Mh] Termos MeSH secundário: Difosfato de Adenosina/metabolismo
Trifosfato de Adenosina/metabolismo
Animais
Transporte Biológico
Feminino
Expressão Gênica
Células Secretoras de Glucagon/patologia
Glucoquinase/deficiência
Intolerância à Glucose/genética
Intolerância à Glucose/patologia
Hipoglicemia/genética
Hipoglicemia/patologia
Insulina/metabolismo
Canais KATP/genética
Canais KATP/metabolismo
Fígado/metabolismo
Masculino
Camundongos
Camundongos Knockout
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Insulin); 0 (KATP Channels); 61D2G4IYVH (Adenosine Diphosphate); 8L70Q75FXE (Adenosine Triphosphate); 9007-92-5 (Glucagon); EC 2.7.1.2 (Glucokinase); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180209
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-018-03034-0


  2 / 1679 MEDLINE  
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[PMID]:29427588
[Au] Autor:Nishimura-Danjobara Y; Oyama K; Yokoigawa K; Oyama Y
[Ad] Endereço:Department of Food Science, Faculty of Bioscience and Bioindustry, Tokushima University, Tokushima 770-8513, Japan.
[Ti] Título:Hyperpolarization by N-(3-oxododecanoyl)-l-homoserine-lactone, a quorum sensing molecule, in rat thymic lymphocytes.
[So] Source:Chem Biol Interact;283:91-96, 2018 Mar 01.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:To study the adverse effects of N-(3-oxododecanoyl)-l-homoserine-lactone (ODHL), a quorum sensing molecule, on mammalian host cells, its effect on membrane potential was examined in rat thymic lymphocytes using flow cytometric techniques with a voltage-sensitive fluorescent probe. As 3-300 µM ODHL elicited hyperpolarization, it is likely that it increases membrane K permeability because hyperpolarization is directly linked to changing K gradient across membranes, but not Na and Cl gradients. ODHL did not increase intracellular Ca concentration. ODHL also produced a response in the presence of an intracellular Zn chelator. Thus, it is unlikely that intracellular Ca and Zn are attributed to the response. Quinine, a non-specific K channel blocker, greatly reduced hyperpolarization. However, because charybdotoxin, tetraethylammonium chloride, 4-aminopyridine, and glibenclamide did not affect it, it is pharmacologically hypothesized that Ca -activated K channels, voltage-gated K channels, and ATP-sensitive K channels are not involved in ODHL-induced hyperpolarization. Although the K channels responsible for ODHL-induced hyperpolarization have not been identified, it is suggested that ODHL can elicit hyperpolarization in mammalian host cells, disturbing cellular functions.
[Mh] Termos MeSH primário: 4-Butirolactona/análogos & derivados
Polaridade Celular/efeitos dos fármacos
Homosserina/análogos & derivados
Percepção de Quorum/efeitos dos fármacos
[Mh] Termos MeSH secundário: 4-Butirolactona/farmacologia
Animais
Cálcio/metabolismo
Charibdotoxina/farmacologia
Citometria de Fluxo
Glibureto/farmacologia
Homosserina/farmacologia
Canais KATP/metabolismo
Linfócitos/citologia
Linfócitos/efeitos dos fármacos
Linfócitos/metabolismo
Permeabilidade/efeitos dos fármacos
Potássio/metabolismo
Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo
Quinina/farmacologia
Ratos
Ratos Wistar
Timócitos/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KATP Channels); 0 (N-(3-oxododecanoyl)homoserine lactone); 0 (Potassium Channels, Voltage-Gated); 115422-61-2 (Charybdotoxin); 6KA95X0IVO (Homoserine); A7V27PHC7A (Quinine); OL659KIY4X (4-Butyrolactone); RWP5GA015D (Potassium); SX6K58TVWC (Glyburide); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180211
[St] Status:MEDLINE


  3 / 1679 MEDLINE  
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[PMID]:28456767
[Au] Autor:Almeida RT; Galdino G; Perez AC; Silva G; Romero TR; Duarte ID
[Ad] Endereço:Department of Pharmacology, Institute of Biological Sciences, Federal University of Belo Horizonte, Minas Gerais, Brazil. imitri@icb.ufmg.br.
[Ti] Título:St36 electroacupuncture activates nNOS, iNOS and ATP-sensitive potassium channels to promote orofacial antinociception in rats.
[So] Source:J Physiol Pharmacol;68(1):27-33, 2017 Feb.
[Is] ISSN:1899-1505
[Cp] País de publicação:Poland
[La] Idioma:eng
[Ab] Resumo:Orofacial pain is pain perceived in the face and/or oral cavity, generally caused by diseases or disorders of regional structures, by dysfunction of the nervous system, or through referral from distant sources. Treatment of orofacial pain is mainly pharmacological, but it has increased the number of reports demonstrating great clinical results with the use of non-pharmacological therapies, among them electroacupuncture. However, the mechanisms involved in the electroacupuncture are not well elucidated. Thus, the present study investigate the involvement of the nitric oxide synthase (NOS) and ATP sensitive K channels (KATP) in the antinociception induced by electroacupuncture (EA) at acupoint St36. Thermal nociception was applied in the vibrissae region of rats, and latency time for face withdrawal was measured. Electrical stimulation of acupoint St36 for 20 minutes reversed the thermal withdrawal latency and this effect was maintained for 150 min. Intraperitoneal administration of specific inhibitors of neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) and a KATP channels blocker reversed the antinociception induced by EA. Furthermore, nitrite concentration in cerebrospinal fluid (CSF) and plasma, increased 4 and 3-fold higher, respectively, after EA. This study suggests that NO participates of antinociception induced by EA by nNOS, iNOS and ATP-sensitive K channels activation.
[Mh] Termos MeSH primário: Pontos de Acupuntura
Eletroacupuntura
Dor Facial/terapia
Manejo da Dor
[Mh] Termos MeSH secundário: Animais
Dor Facial/fisiopatologia
Temperatura Alta/efeitos adversos
Canais KATP/antagonistas & inibidores
Canais KATP/fisiologia
Masculino
Óxido Nítrico Sintase Tipo I/antagonistas & inibidores
Óxido Nítrico Sintase Tipo I/fisiologia
Óxido Nítrico Sintase Tipo II/antagonistas & inibidores
Óxido Nítrico Sintase Tipo II/fisiologia
Nitritos/sangue
Nitritos/líquido cefalorraquidiano
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KATP Channels); 0 (Nitrites); EC 1.14.13.39 (Nitric Oxide Synthase Type I); EC 1.14.13.39 (Nitric Oxide Synthase Type II); EC 1.14.13.39 (Nos2 protein, rat)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


  4 / 1679 MEDLINE  
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[PMID]:29235789
[Au] Autor:Danylovych YV; Chunikhin AY; Danylovych GV; Kolomiets OV
[Ti] Título:The use of the Petri net method in the simulation modeling of mitochondrial swelling.
[So] Source:Ukr Biochem J;88(4):66-74, 2016 Jul-Aug.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:Using photon correlation spectroscopy, which allows investigating changes in the hydrodynamic dia­meter of the particles in suspension, it was shown that ultrahigh concentrations of Ca2+ (over 10 mM) induce swelling of isolated mitochondria. An increase in hydrodynamic diameter was caused by an increase of non-specific mitochondrial membrane permeability to Ca ions, matrix Ca2+ overload, activation of ATP- and Ca2+-sensitive K+-channels, as well as activation of cyclosporin-sensitive permeability transition pore. To formalize the experimental data and to assess conformity of experimental results with theoretical predictions we developed a simulation model using the hybrid functional Petri net method.
[Mh] Termos MeSH primário: Cálcio/farmacologia
Ciclosporina/farmacologia
Mitocôndrias/efeitos dos fármacos
Dilatação Mitocondrial/efeitos dos fármacos
Modelos Biológicos
[Mh] Termos MeSH secundário: Animais
Cálcio/metabolismo
Cátions Bivalentes
Permeabilidade da Membrana Celular/efeitos dos fármacos
Simulação por Computador
Feminino
Transporte de Íons
Canais KATP/metabolismo
Cinética
Mitocôndrias/metabolismo
Proteínas de Transporte da Membrana Mitocondrial/metabolismo
Miométrio/química
Miométrio/metabolismo
Canais de Potássio Cálcio-Ativados/metabolismo
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cations, Divalent); 0 (KATP Channels); 0 (Mitochondrial Membrane Transport Proteins); 0 (Potassium Channels, Calcium-Activated); 0 (mitochondrial permeability transition pore); 83HN0GTJ6D (Cyclosporine); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.04.066


  5 / 1679 MEDLINE  
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[PMID]:28977595
[Au] Autor:Huang WQ; Guo JH; Zhang XH; Yu MK; Chung YW; Ruan YC; Chan HC
[Ad] Endereço:Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
[Ti] Título:Glucose-Sensitive CFTR Suppresses Glucagon Secretion by Potentiating KATP Channels in Pancreatic Islet α Cells.
[So] Source:Endocrinology;158(10):3188-3199, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The secretion of glucagon by islet α cells is normally suppressed by high blood glucose, but this suppressibility is impaired in patients with diabetes or cystic fibrosis (CF), a disease caused by mutations in the gene encoding CF transmembrane conductance regulator (CFTR), a cyclic adenosine monophosphate-activated Cl- channel. However, precisely how glucose regulates glucagon release remains controversial. Here we report that elevated glucagon secretion, together with increased glucose-induced membrane depolarization and Ca2+ response, is found in CFTR mutant (DF508) mice/islets compared with the wild-type. Overexpression of CFTR in AlphaTC1-9 cells results in membrane hyperpolarization and reduced glucagon release, which can be reversed by CFTR inhibition. CFTR is found to potentiate the adenosine triphosphate-sensitive K+ (KATP) channel because membrane depolarization and whole-cell currents sensitive to KATP blockers are significantly greater in wild-type/CFTR-overexpressed α cells compared with that in DF508/non-overexpressed cells. KATP knockdown also reverses the suppressive effect of CFTR overexpression on glucagon secretion. The results reveal that by potentiating KATP channels, CFTR acts as a glucose-sensing negative regulator of glucagon secretion in α cells, a defect of which may contribute to glucose intolerance in CF and other types of diabetes.
[Mh] Termos MeSH primário: Regulador de Condutância Transmembrana em Fibrose Cística/antagonistas & inibidores
Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia
Células Secretoras de Glucagon/secreção
Glucagon/secreção
Glucose/farmacologia
Canais KATP/fisiologia
[Mh] Termos MeSH secundário: Animais
Cálcio/análise
Linhagem Celular
Cloretos/metabolismo
Fibrose Cística/complicações
Fibrose Cística/genética
Regulador de Condutância Transmembrana em Fibrose Cística/genética
Expressão Gênica
Técnicas de Silenciamento de Genes
Glucagon/antagonistas & inibidores
Glucagon/sangue
Células Secretoras de Glucagon/fisiologia
Intolerância à Glucose/complicações
Camundongos
Camundongos Mutantes
Mutação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chlorides); 0 (KATP Channels); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator); 9007-92-5 (Glucagon); IY9XDZ35W2 (Glucose); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00282


  6 / 1679 MEDLINE  
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[PMID]:28977592
[Au] Autor:Sun X; Yi Y; Xie W; Liang B; Winter MC; He N; Liu X; Luo M; Yang Y; Ode KL; Uc A; Norris AW; Engelhardt JF
[Ad] Endereço:Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242.
[Ti] Título:CFTR Influences Beta Cell Function and Insulin Secretion Through Non-Cell Autonomous Exocrine-Derived Factors.
[So] Source:Endocrinology;158(10):3325-3338, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although ß-cell dysfunction in cystic fibrosis (CF) leads to diabetes, the mechanism by which the cystic fibrosis transmembrane conductance regulator (CFTR) channel influences islet insulin secretion remains debated. We investigated the CFTR-dependent islet-autonomous mechanisms affecting insulin secretion by using islets isolated from CFTR knockout ferrets. Total insulin content was lower in CF as compared with wild-type (WT) islets. Furthermore, glucose-stimulated insulin secretion (GSIS) was impaired in perifused neonatal CF islets, with reduced first, second, and amplifying phase secretion. Interestingly, CF islets compensated for reduced insulin content under static low-glucose conditions by secreting a larger fraction of islet insulin than WT islets, probably because of elevated SLC2A1 transcripts, increased basal inhibition of adenosine triphosphate-sensitive potassium channels (K-ATP), and elevated basal intracellular Ca2+. Interleukin (IL)-6 secretion by CF islets was higher relative to WT, and IL-6 treatment of WT ferret islets produced a CF-like phenotype with reduced islet insulin content and elevated percentage insulin secretion in low glucose. CF islets exhibited altered expression of INS, CELA3B, and several ß-cell maturation and proliferation genes. Pharmacologic inhibition of CFTR reduced GSIS by WT ferret and human islets but similarly reduced insulin secretion and intracellular Ca2+ in CFTR knockout ferret islets, indicating that the mechanism of action is not through CFTR. Single-molecule fluorescent in situ hybridization, on isolated ferret and human islets and ferret pancreas, demonstrated that CFTR RNA colocalized within KRT7+ ductal cells but not endocrine cells. These results suggest that CFTR affects ß-cell function via a paracrine mechanism involving proinflammatory factors secreted from islet-associated exocrine-derived cell types.
[Mh] Termos MeSH primário: Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia
Células Secretoras de Insulina/fisiologia
Insulina/secreção
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Cálcio/análise
Regulador de Condutância Transmembrana em Fibrose Cística/deficiência
Regulador de Condutância Transmembrana em Fibrose Cística/genética
Feminino
Furões/genética
Técnicas de Inativação de Genes
Glucose/farmacologia
Seres Humanos
Hibridização in Situ Fluorescente
Insulina/análise
Interleucina-6/farmacologia
Interleucina-6/secreção
Ilhotas Pancreáticas/química
Ilhotas Pancreáticas/efeitos dos fármacos
Ilhotas Pancreáticas/secreção
Canais KATP/antagonistas & inibidores
Masculino
RNA/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (Interleukin-6); 0 (KATP Channels); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator); 63231-63-0 (RNA); IY9XDZ35W2 (Glucose); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00187


  7 / 1679 MEDLINE  
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[PMID]:28893911
[Au] Autor:Aziz Q; Li Y; Anderson N; Ojake L; Tsisanova E; Tinker A
[Ad] Endereço:From the Heart Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom.
[Ti] Título:Molecular and functional characterization of the endothelial ATP-sensitive potassium channel.
[So] Source:J Biol Chem;292(43):17587-17597, 2017 Oct 27.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ATP-sensitive potassium (K ) channels are widely expressed in the cardiovascular system, where they regulate a range of biological activities by linking cellular metabolism with membrane excitability. K channels in vascular smooth muscle have a well-defined role in regulating vascular tone. K channels are also thought to be expressed in vascular endothelial cells, but their presence and function in this context are less clear. As a result, we aimed to investigate the molecular composition and physiological role of endothelial K channels. We first generated mice with an endothelial specific deletion of the channel subunit Kir6.1 (eKO) using cre-loxP technology. Data from qRT-PCR, patch clamp, coronary perfusion Langendorff heart experiments, and endothelial cell Ca imaging comparing eKO and wild-type mice show that Kir6.1-containing K channels are indeed present in vascular endothelium. An increase in intracellular [Ca ], which is central to changes in endothelial function such as mediator release, at least partly contributes to the endothelium-dependent vasorelaxation induced by the K channel opener pinacidil. The absence of Kir6.1 did not elevate basal coronary perfusion pressure in eKO mice. However, vasorelaxation was impaired during hypoxia in the coronary circulation, and this resulted in greater cardiac injury during ischemia-reperfusion. The response to adenosine receptor stimulation was impaired in eKO mice in single cells in patch clamp recordings and in the intact coronary circulation. Our data support the existence of an endothelial K channel that contains Kir6.1, is involved in vascular reactivity in the coronary circulation, and has a protective role in ischemia reperfusion.
[Mh] Termos MeSH primário: Sinalização do Cálcio
Cálcio/metabolismo
Circulação Coronária
Endotélio Vascular/metabolismo
Canais KATP/metabolismo
Traumatismo por Reperfusão Miocárdica/metabolismo
Vasodilatação
[Mh] Termos MeSH secundário: Animais
Endotélio Vascular/fisiopatologia
Canais KATP/genética
Camundongos
Camundongos Knockout
Traumatismo por Reperfusão Miocárdica/genética
Traumatismo por Reperfusão Miocárdica/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KATP Channels); 0 (uK-ATP-1 potassium channel); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.810325


  8 / 1679 MEDLINE  
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[PMID]:28842488
[Au] Autor:Cooper PE; McClenaghan C; Chen X; Stary-Weinzinger A; Nichols CG
[Ad] Endereço:From the Department of Cell Biology and Physiology and Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri 63110 and.
[Ti] Título:Conserved functional consequences of disease-associated mutations in the slide helix of Kir6.1 and Kir6.2 subunits of the ATP-sensitive potassium channel.
[So] Source:J Biol Chem;292(42):17387-17398, 2017 Oct 20.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cantu syndrome (CS) is a condition characterized by a range of anatomical defects, including cardiomegaly, hyperflexibility of the joints, hypertrichosis, and craniofacial dysmorphology. CS is associated with multiple missense mutations in the genes encoding the regulatory sulfonylurea receptor 2 (SUR2) subunits of the ATP-sensitive K (K ) channel as well as two mutations (V65M and C176S) in the Kir6.1 ( ) subunit. Previous analysis of leucine and alanine substitutions at the Val-65-equivalent site (Val-64) in Kir6.2 indicated no major effects on channel function. In this study, we characterized the effects of both valine-to-methionine and valine-to-leucine substitutions at this position in both Kir6.1 and Kir6.2 using ion flux and patch clamp techniques. We report that methionine substitution, but not leucine substitution, results in increased open state stability and hence significantly reduced ATP sensitivity and a marked increase of channel activity in the intact cell irrespective of the identity of the coassembled SUR subunit. Sulfonylurea inhibitors, such as glibenclamide, are potential therapies for CS. However, as a consequence of the increased open state stability, both Kir6.1(V65M) and Kir6.2(V64M) mutations essentially abolish high-affinity sensitivity to the K blocker glibenclamide in both intact cells and excised patches. This raises the possibility that, at least for some CS mutations, sulfonylurea therapy may not prove to be successful and highlights the need for detailed pharmacogenomic analyses of CS mutations.
[Mh] Termos MeSH primário: Cardiomegalia/metabolismo
Hipertricose/metabolismo
Canais KATP/metabolismo
Mutação de Sentido Incorreto
Osteocondrodisplasias/metabolismo
Canais de Potássio Corretores do Fluxo de Internalização/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Células COS
Cardiomegalia/genética
Cercopithecus aethiops
Glibureto/farmacologia
Seres Humanos
Hipertricose/genética
Canais KATP/química
Canais KATP/genética
Camundongos
Osteocondrodisplasias/genética
Técnicas de Patch-Clamp
Canais de Potássio Corretores do Fluxo de Internalização/química
Canais de Potássio Corretores do Fluxo de Internalização/genética
Estabilidade Proteica/efeitos dos fármacos
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KATP Channels); 0 (Kir6.2 channel); 0 (Potassium Channels, Inwardly Rectifying); 0 (uK-ATP-1 potassium channel); SX6K58TVWC (Glyburide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171028
[Lr] Data última revisão:
171028
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170827
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.804971


  9 / 1679 MEDLINE  
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[PMID]:28768770
[Au] Autor:Wu Y; Fortin DA; Cochrane VA; Chen PC; Shyng SL
[Ad] Endereço:From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239 and.
[Ti] Título:NMDA receptors mediate leptin signaling and regulate potassium channel trafficking in pancreatic ß-cells.
[So] Source:J Biol Chem;292(37):15512-15524, 2017 Sep 15.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:NMDA receptors (NMDARs) are Ca -permeant, ligand-gated ion channels activated by the excitatory neurotransmitter glutamate and have well-characterized roles in the nervous system. The expression and function of NMDARs in pancreatic ß-cells, by contrast, are poorly understood. Here, we report a novel function of NMDARs in ß-cells. Using a combination of biochemistry, electrophysiology, and imaging techniques, we now show that NMDARs have a key role in mediating the effect of leptin to modulate ß-cell electrical activity by promoting AMP-activated protein kinase (AMPK)-dependent trafficking of K and Kv2.1 channels to the plasma membrane. Blocking NMDAR activity inhibited the ability of leptin to activate AMPK, induce K and Kv2.1 channel trafficking, and promote membrane hyperpolarization. Conversely, activation of NMDARs mimicked the effect of leptin, causing Ca influx, AMPK activation, and increased trafficking of K and Kv2.1 channels to the plasma membrane, and triggered membrane hyperpolarization. Moreover, leptin potentiated NMDAR currents and triggered NMDAR-dependent Ca influx. Importantly, NMDAR-mediated signaling was observed in rat insulinoma 832/13 cells and in human ß-cells, indicating that this pathway is conserved across species. The ability of NMDARs to regulate potassium channel surface expression and thus, ß-cell excitability provides mechanistic insight into the recently reported insulinotropic effects of NMDAR antagonists and therefore highlights the therapeutic potential of these drugs in managing type 2 diabetes.
[Mh] Termos MeSH primário: Células Secretoras de Insulina/metabolismo
Canais KATP/metabolismo
Leptina/metabolismo
Receptores de N-Metil-D-Aspartato/agonistas
Canais de Potássio Shab/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/antagonistas & inibidores
Proteínas Quinases Ativadas por AMP/metabolismo
Adulto
Animais
Biotinilação
Sinalização do Cálcio/efeitos dos fármacos
Linhagem Celular Tumoral
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Células Cultivadas
Seres Humanos
Insulina/secreção
Células Secretoras de Insulina/citologia
Células Secretoras de Insulina/efeitos dos fármacos
Células Secretoras de Insulina/secreção
Ligantes
Moduladores de Transporte de Membrana/farmacologia
Transporte Proteico/efeitos dos fármacos
Ratos
Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
Receptores de N-Metil-D-Aspartato/metabolismo
Transdução de Sinais/efeitos dos fármacos
Propriedades de Superfície
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insulin); 0 (KATP Channels); 0 (KCNB1 protein, human); 0 (Kcnb1 protein, rat); 0 (Leptin); 0 (Ligands); 0 (Membrane Transport Modulators); 0 (Receptors, N-Methyl-D-Aspartate); 0 (Shab Potassium Channels); EC 2.7.11.31 (AMP-Activated Protein Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.802249


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[PMID]:28667054
[Au] Autor:Swan KW; Song BM; Chen AL; Chen TJ; Chan RA; Guidry BT; Katakam PVG; Kerut EK; Giles TD; Kadowitz PJ
[Ad] Endereço:Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana.
[Ti] Título:Analysis of decreases in systemic arterial pressure and heart rate in response to the hydrogen sulfide donor sodium sulfide.
[So] Source:Am J Physiol Heart Circ Physiol;313(4):H732-H743, 2017 Oct 01.
[Is] ISSN:1522-1539
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The actions of hydrogen sulfide (H S) on the heart and vasculature have been extensively reported. However, the mechanisms underlying the effects of H S are unclear in the anesthetized rat. The objective of the present study was to investigate the effect of H S on the electrocardiogram and examine the relationship between H S-induced changes in heart rate (HR), mean arterial pressure (MAP), and respiratory function. Intravenous administration of the H S donor Na S in the anesthetized Sprague-Dawley rat decreased MAP and HR and produced changes in respiratory function. The administration of Na S significantly increased the RR interval at some doses but had no effect on PR or corrected QT( )-B intervals. In experiments where respiration was maintained with a mechanical ventilator, we observed that Na S-induced decreases in MAP and HR were independent of respiration. In experiments where respiration was maintained by mechanical ventilation and HR was maintained by cardiac pacing, Na S-induced changes in MAP were not significantly altered, whereas changes in HR were abolished. Coadministration of glybenclamide significantly increased MAP and HR responses at some doses, but methylene blue, diltiazem, and ivabradine had no significant effect compared with control. The decreases in MAP and HR in response to Na S could be dissociated and were independent of changes in respiratory function, ATP-sensitive K channels, methylene blue-sensitive mechanism involving L-type voltage-sensitive Ca channels, or hyperpolarization-activated cyclic nucleotide-gated channels. Cardiovascular responses observed in spontaneously hypertensive rats were more robust than those in Sprague-Dawley rats. H S is a gasotransmitter capable of producing a decrease in mean arterial pressure and heart rate. The hypotensive and bradycardic effects of H S can be dissociated, as shown with cardiac pacing experiments. Responses were not blocked by diltiazem, ivabradine, methylene blue, or glybenclamide.
[Mh] Termos MeSH primário: Pressão Arterial/efeitos dos fármacos
Frequência Cardíaca/efeitos dos fármacos
Sulfeto de Hidrogênio/farmacologia
Sulfetos/farmacologia
[Mh] Termos MeSH secundário: Animais
Canais de Cálcio Tipo L/efeitos dos fármacos
Estimulação Cardíaca Artificial
Eletrocardiografia/efeitos dos fármacos
Glibureto/farmacologia
Hipoglicemiantes/farmacologia
Canais KATP/efeitos dos fármacos
Masculino
Bloqueadores dos Canais de Potássio/farmacologia
Ratos
Ratos Endogâmicos SHR
Ratos Sprague-Dawley
Respiração Artificial
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels, L-Type); 0 (Hypoglycemic Agents); 0 (KATP Channels); 0 (Potassium Channel Blockers); 0 (Sulfides); SX6K58TVWC (Glyburide); YGR27ZW0Y7 (sodium sulfide); YY9FVM7NSN (Hydrogen Sulfide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170702
[St] Status:MEDLINE
[do] DOI:10.1152/ajpheart.00729.2016



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