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Article ; Online: CaMKII Modulates the Cardiac Transient Outward K

Alday, Aintzane / Ahyayauch, Hasna / Fernández-López, Victor / Echeazarra, Leyre / Urrutia, Janire / Casis, Oscar / Gallego, Mónica

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

2020 Volume 54, Issue 1, Page(s) 27–39

Abstract: Background/aims: To test whether the physiological regulation of the cardiac Kv4 channels by the Ca: Methods: Ventricular myocytes were freshly isolated from Sprague-Dawley rats. I: Results: Patch-Clamp recordings in control conditions and after ... ...

Abstract	Background/aims: To test whether the physiological regulation of the cardiac Kv4 channels by the Ca Methods: Ventricular myocytes were freshly isolated from Sprague-Dawley rats. I Results: Patch-Clamp recordings in control conditions and after lipid raft or caveolae disruption show that the CaMKII-Kv4 channel complex must associate in non-caveolar lipid rafts to be functional. Separation in density gradients, co-immunoprecipitation and electron microscopy show that there are two Kv4 channel populations: one located in caveolae, that is CaMKII independent, and another one located in planar membrane rafts, which is bound to CaMKII. Conclusion: CaMKII regulates only the Kv4 channel population located in non-caveolar lipid rafts. Thus, the regulation of cardiac Kv4 channels in rat and human ventricle depends on their subcellular localization.
MeSH term(s)	Animals ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/analysis ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Caveolae/metabolism ; Cells, Cultured ; Humans ; Ion Transport ; Membrane Microdomains/metabolism ; Myocytes, Cardiac/metabolism ; Potassium/metabolism ; Protein Interaction Maps ; Rats, Sprague-Dawley ; Shal Potassium Channels/analysis ; Shal Potassium Channels/metabolism
Chemical Substances	Shal Potassium Channels ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17) ; Potassium (RWP5GA015D)
Language	English
Publishing date	2020-01-28
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.33594/000000203
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Article: Adrenergic regulation of cardiac ionic channels: role of membrane microdomains in the regulation of kv4 channels.

Gallego, Mónica / Alday, Aintzane / Alonso, Hiart / Casis, Oscar

Biochimica et biophysica acta

2014 Volume 1838, Issue 2, Page(s) 692–699

Abstract: The heart must constantly adapt its activity to the needs of the body. In any potentially dangerous or physically demanding situation the activated sympathetic nervous system leads a very fast cardiac response. Under these circumstances, α1-adrenergic ... ...

Abstract	The heart must constantly adapt its activity to the needs of the body. In any potentially dangerous or physically demanding situation the activated sympathetic nervous system leads a very fast cardiac response. Under these circumstances, α1-adrenergic receptors activate intracellular signaling pathways that finally phosphorylate the caveolae-located subpopulation of Kv4 channels and reduce the transient outward K(+) current (Ito) amplitude. This reduction changes the shape of the cardiac action potential and makes the plateau phase to start at higher voltages. This means that there are more calcium ions entering the myocyte and the result is an increase in the strength of the contraction. However, an excessive reduction of Ito could dangerously prolong action potential duration and this could cause arrhythmias when the heart rate is high. This excessive current reduction does not occur because there is a second population of Ito channels located in non-caveolar membrane rafts that are not accessible for α1-AR mediated regulation. Thus, the location of the components of a given transduction signaling pathway in membrane domains determines the correct and safe behavior of the heart. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.
MeSH term(s)	Animals ; Heart/physiology ; Humans ; Ion Channels/metabolism ; Membrane Microdomains/metabolism ; Receptors, Adrenergic, alpha-1/metabolism ; Shal Potassium Channels/metabolism
Chemical Substances	Ion Channels ; Receptors, Adrenergic, alpha-1 ; Shal Potassium Channels
Language	English
Publishing date	2014-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamem.2013.06.025
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Article ; Online: Detection and Prioritization of Developmentally Neurotoxic and/or Neurotoxic Compounds Using Zebrafish.

Quevedo, Celia / Behl, Mamta / Ryan, Kristen / Paules, Richard S / Alday, Aintzane / Muriana, Arantza / Alzualde, Ainhoa

Toxicological sciences : an official journal of the Society of Toxicology

2018 Volume 168, Issue 1, Page(s) 225–240

Abstract: The standard methods for toxicity testing using rodent models cannot keep pace with the increasing number of chemicals in our environment due to time and resource limitations. Hence, there is an unmet need for fast, sensitive, and cost-effective ... ...

Abstract	The standard methods for toxicity testing using rodent models cannot keep pace with the increasing number of chemicals in our environment due to time and resource limitations. Hence, there is an unmet need for fast, sensitive, and cost-effective alternate models to reliably predict toxicity. As part of Tox21 Phase III's effort, a 90-compound library was created and made available to researchers to screen for neurotoxicants using novel technology and models. The chemical library was evaluated in zebrafish in a dose-range finding test for embryo-toxicity (ie, mortality or morphological alterations induced by each chemical). In addition, embryos exposed to the lowest effect level and nonobservable effect level were used to measure the internal concentration of the chemicals within the embryos by bioanalysis. Finally, considering the lowest effect level as the highest testing concentration, a functional assay was performed based on locomotor activity alteration in response to light-dark changes. The quality control chemicals included in the library, ie, negative controls and replicated chemicals, indicate that the assays performed were reliable. The use of analytical chemistry pointed out the importance of measuring chemical concentration inside embryos, and in particular, in the case of negative chemicals to avoid false negative classification. Overall, the proposed approach presented a good sensitivity and supports the inclusion of zebrafish assays as a reliable, relevant, and efficient screening tool to identify, prioritize, and evaluate chemical toxicity.
MeSH term(s)	Animals ; Biological Assay ; Embryo, Nonmammalian/drug effects ; Flame Retardants/toxicity ; Larva/drug effects ; Motor Activity/drug effects ; Neurotoxicity Syndromes ; Pesticides/toxicity ; Pharmaceutical Preparations ; Small Molecule Libraries ; Swimming ; Toxicity Tests/methods ; Zebrafish/growth & development
Chemical Substances	Flame Retardants ; Pesticides ; Pharmaceutical Preparations ; Small Molecule Libraries
Language	English
Publishing date	2018-12-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfy291
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Zs.A 1709: Show issues

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Article ; Online: Toxicity profiling of flame retardants in zebrafish embryos using a battery of assays for developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity toward human relevance.

Alzualde, Ainhoa / Behl, Mamta / Sipes, Nisha S / Hsieh, Jui-Hua / Alday, Aintzane / Tice, Raymond R / Paules, Richard S / Muriana, Arantza / Quevedo, Celia

Neurotoxicology and teratology

2018 Volume 70, Page(s) 40–50

Abstract: Following the voluntary phase-out of brominated flame retardants (BFRs) due to their environmental persistence and toxicity, the organophosphorus flame retardants (OPFRs) are emerging replacements. However, there is limited information on the potential ... ...

Abstract	Following the voluntary phase-out of brominated flame retardants (BFRs) due to their environmental persistence and toxicity, the organophosphorus flame retardants (OPFRs) are emerging replacements. However, there is limited information on the potential human health effects of the OPFRs. Zebrafish embryos are a viable vertebrate model organism with many advantages for high throughput testing toward human hazard assessment. We utilized zebrafish embryos to assess developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity, of eight replacement OPFRs: (triphenyl phosphate [TPHP], isopropylated phenyl phosphate [IPP], 2-ethylhexyl diphenyl phosphate [EHDP], tert-butylated phenyl diphenyl phosphate [BPDP], trimethyl phenyl phosphate [TMPP], isodecyl diphenyl phosphate [IDDP], tris(1,3-dichloroisopropyl) phosphate [TDCIPP], and tris(2-chloroethyl) phosphate [TCEP]) and two BFRs (3,3',5,5'- tetrabromobisphenol A [TBBPA] and 2,2'4,4'-brominated diphenyl ether [BDE-47]). To determine potential effects on teratogenicity, embryos were exposed to flame retardants (FRs) at 4 h post fertilization (hpf) to 4 days post fertilization (dpf) and morphological alterations and corresponding survival were evaluated at 2 and 4 dpf. Internal concentrations were measured in larvae used in this assay by liquid chromatography-mass spectrometry. Locomotor activity was assessed in larvae treated for 48 h (from 3 dpf to 5 dpf), followed by hepatotoxicity evaluation. Finally, alterations in heart rate and rhythmicity were assessed to determine cardiotoxicity in 48 hpf embryos exposed to compounds for 3 h. Results suggest that several OPFRs (BPDP, EHDP; IPP, TMPP; TPHP and TDCIPP) produced adverse effects in multiple target organs at concentrations comparable to the two BFRs. As these OPFRs have the capacity to disrupt an integrated vertebrate model, they potentially have the capacity to affect mammalian biology. Then, we compared the lowest effective levels (LEL) in zebrafish with estimated or measured human plasma concentrations using biomonitoring data (human plasma, breast milk, handwipe samples and house dust) and a high throughput toxicokinetic (HTTK) model. Results indicate that for some compounds, the nominal LELs were within the range of human exposures, while internal LELs in zebrafish are above internal exposures in humans. These findings demonstrate the value of the zebrafish model as a relevant screening tool and support the need for further hazard characterization of the OPFRs.
MeSH term(s)	Animals ; Cardiotoxicity/etiology ; Embryonic Development/drug effects ; Flame Retardants/toxicity ; Humans ; Neurotoxicity Syndromes/etiology ; Organophosphates/pharmacology ; Organophosphates/toxicity ; Organophosphorus Compounds/toxicity ; Zebrafish
Chemical Substances	Flame Retardants ; Organophosphates ; Organophosphorus Compounds ; triphenyl phosphate (YZE19Z66EA) ; trimethyl phosphate (Z1E45TMW1Z)
Language	English
Publishing date	2018-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639165-5
ISSN	1872-9738 ; 0892-0362
ISSN (online)	1872-9738
ISSN	0892-0362
DOI	10.1016/j.ntt.2018.10.002
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Zs.A 1626: Show issues

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Article ; Online: α1-adrenoceptors regulate only the caveolae-located subpopulation of cardiac K(V)4 channels.

Alday, Aintzane / Urrutia, Janire / Gallego, Mónica / Casis, Oscar

Channels (Austin, Tex.)

2010 Volume 4, Issue 3, Page(s) 168–178

Abstract: In ventricular myocytes, α1-AR stimulates Gαs proteins and reduces the transient outward K(+) current (I(to)) via a cAMP/PKA-mediated pathway and thus regulates cardiac contraction and excitability. This I(to) reduction is compartmentalized and limited ... ...

Abstract	In ventricular myocytes, α1-AR stimulates Gαs proteins and reduces the transient outward K(+) current (I(to)) via a cAMP/PKA-mediated pathway and thus regulates cardiac contraction and excitability. This I(to) reduction is compartmentalized and limited to discrete membrane regions since PKA-dependent phosphorylation of the I(to) channels after α1-AR stimulation requires the integrity of both the sarcoplasmic membrane and the cytoskeleton. The aim of this work was to investigate the mechanisms involved in the compartmentalization of the PKA-dependent modulation of I(to) in response to α1-AR activation. I(to) current recordings were performed by the Patch-Clamp technique. Membrane rafts from isolated ventricular myocytes were extracted by centrifugation in a sucrose density gradient. The different proteins were visualized by western blot and protein-protein interactions determined by coimmunoprecipitation experiments. Localization of I(to) channel in caveolae, particular subtypes of membrane rafts, was achieved by electron microscopy. Patch-Clamp recordings show that a functional supramolecular complex, kept together by the Akinase anchoring protein AKAP100, exist in caveolae in living myocytes. Density gradients and immunoprecipitation experiments show that the components of the α1-AR/I(to) pathway localize in caveolae, forming two different groups of proteins. The K(V)4.2/K(V)4.3 channel forms a supramolecular complex with PKA through AKAP100 and is attached to caveolae by interacting with caveolin-3. On the other hand, α1-AR, Gαs and adenylate cyclase gather in a second group also connected to caveolin-3. Therefore, both groups of preassembled proteins are maintained in close proximity by caveolin-3. A different I(to) channel population localizes in non-caveolar membrane rafts and is not sensitive to α1-adrenergic regulation.
MeSH term(s)	Animals ; Caveolae ; Caveolin 3/metabolism ; Cell Compartmentation ; Heart Ventricles/cytology ; Membrane Microdomains ; Multiprotein Complexes/metabolism ; Muscle Cells/chemistry ; Muscle Cells/metabolism ; Myocardium/chemistry ; Patch-Clamp Techniques ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic/physiology ; Receptors, Adrenergic, alpha-1/physiology ; Shal Potassium Channels/metabolism
Chemical Substances	Adra1a protein, rat ; Caveolin 3 ; Multiprotein Complexes ; Receptors, Adrenergic ; Receptors, Adrenergic, alpha-1 ; Shal Potassium Channels
Language	English
Publishing date	2010-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2262854-X
ISSN	1933-6969 ; 1933-6950
ISSN (online)	1933-6969
ISSN	1933-6950
DOI	10.4161/chan.4.3.11479
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Article ; Online: Ionic channels underlying the ventricular action potential in zebrafish embryo.

Alday, Aintzane / Alonso, Hiart / Gallego, Monica / Urrutia, Janire / Letamendia, Ainhoa / Callol, Carles / Casis, Oscar

Pharmacological research

2014 Volume 84, Page(s) 26–31

Abstract: Over the last years zebrafish has become a popular model in the study of cardiac physiology, pathology and pharmacology. Recently, the application of the 3Rs regulation and the characteristics of the embryo have reduced the use of adult zebrafish use in ... ...

Abstract	Over the last years zebrafish has become a popular model in the study of cardiac physiology, pathology and pharmacology. Recently, the application of the 3Rs regulation and the characteristics of the embryo have reduced the use of adult zebrafish use in many studies. However, the zebrafish embryo cardiac physiology is poorly characterized since most works have used indirect techniques and direct recordings of cardiac action potential and ionic currents are scarce. In order to optimize the zebrafish embryo model, we used electrophysiological, pharmacological and immunofluorescence tools to identify the characteristics and the ionic channels involved in the ventricular action potentials of zebrafish embryos. The application of Na(+) or T-type Ca(+2) channel blockers eliminated the cardiac electrical activity, indicating that the action potential upstroke depends on Na(+) and T-type Ca(+2) currents. The plateau phase depends on L-type Ca(+2) channels since it is abolished by specific blockade. The direct channel blockade indicates that the action potential repolarization and diastolic potential depends on ERG K(+) channels. The presence in the embryonic heart of the Nav1.5, Cav1.2, Cav3.2 and ERG channels was also confirmed by immunofluorescence, while the absence of effect of specific blockers and immunostaining indicate that two K(+) repolarizing currents present in human heart, Ito and IKs, are absent in the embryonic zebrafish heart. Our results describe the ionic channels present and its role in the zebrafish embryo heart and support the use of zebrafish embryos to study human diseases and their use for drug testing.
MeSH term(s)	Action Potentials/drug effects ; Action Potentials/physiology ; Animals ; Calcium Channel Blockers/pharmacology ; Embryo, Nonmammalian/physiology ; Heart Ventricles/drug effects ; In Vitro Techniques ; Ion Channels/drug effects ; Ion Channels/physiology ; Sodium Channel Blockers/pharmacology ; Zebrafish
Chemical Substances	Calcium Channel Blockers ; Ion Channels ; Sodium Channel Blockers
Language	English
Publishing date	2014-06
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2014.03.011
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Zs.A 721: Show issues

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Article: Transient outward potassium channel regulation in healthy and diabetic hearts.

Gallego, Mónica / Alday, Aintzane / Urrutia, Janire / Casis, Oscar

Canadian journal of physiology and pharmacology

2009 Volume 87, Issue 2, Page(s) 77–83

Abstract: Diabetic patients have a higher incidence of cardiac arrhythmias, including ventricular fibrillation and sudden death, and show important alterations in the electrocardiogram, most of these related to the repolarization. In myocytes isolated from ... ...

Abstract	Diabetic patients have a higher incidence of cardiac arrhythmias, including ventricular fibrillation and sudden death, and show important alterations in the electrocardiogram, most of these related to the repolarization. In myocytes isolated from diabetic hearts, the transient outward K+ current (Ito) is the repolarizing current that is mainly affected. Type 1 diabetes alters Ito at 3 levels: the recovery of inactivation, the responsiveness to physiologic regulators, and the functional expression of the channel. Diabetes slows down Ito recovery of inactivation because it triggers the switching from fast-recovering Kv4.x channels to the slow-recovering Kv1.4. Diabetic animals also have decreased responsiveness of Ito towards the sympathetic nervous system; thus, the diabetic heart develops a resistance to its physiologic regulator. Finally, diabetes impairs support of various trophic factors required for the functional expression of the channel and reduces Ito amplitude by decreasing the amount of Kv4.2 and Kv4.3 proteins.
MeSH term(s)	Action Potentials ; Animals ; Arrhythmias, Cardiac/metabolism ; Arrhythmias, Cardiac/physiopathology ; Diabetes Complications/metabolism ; Diabetes Complications/physiopathology ; Humans ; Kinetics ; Kv1.4 Potassium Channel/metabolism ; Myocytes, Cardiac/metabolism ; Potassium Channels/metabolism ; Shal Potassium Channels/metabolism ; Sympathetic Nervous System/physiopathology
Chemical Substances	Kv1.4 Potassium Channel ; Potassium Channels ; Shal Potassium Channels
Language	English
Publishing date	2009-02
Publishing country	Canada
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	127527-6
ISSN	1205-7541 ; 0008-4212
ISSN (online)	1205-7541
ISSN	0008-4212
DOI	10.1139/Y08-106
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Zs.A 589: Show issues

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Article ; Online: Mechanisms of IhERG/IKr Modulation by α1-Adrenoceptors in HEK293 Cells and Cardiac Myocytes.

Urrutia, Janire / Alday, Aintzane / Gallego, Mónica / Malagueta-Vieira, L Layse / Aréchiga-Figueroa, Ivan Arael / Casis, Oscar / Sánchez-Chapula, José Antonio

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

2016 Volume 40, Issue 6, Page(s) 1261–1273

Abstract: Background: The rapid delayed rectifier K+ current (IKr), carried by the hERG protein, is one of the main repolarising currents in the human heart and a reduction of this current increases the risk of ventricular fibrillation. α1-adrenoceptors (α1-AR) ... ...

Abstract	Background: The rapid delayed rectifier K+ current (IKr), carried by the hERG protein, is one of the main repolarising currents in the human heart and a reduction of this current increases the risk of ventricular fibrillation. α1-adrenoceptors (α1-AR) activation reduces IKr but, despite the clear relationship between an increase in the sympathetic tone and arrhythmias, the mechanisms underlying the α1-AR regulation of the hERG channel are controversial. Thus, we aimed to investigate the mechanisms by which α1-AR stimulation regulates IKr. Methods: α1-adrenoceptors, hERG channels, auxiliary subunits minK and MIRP1, the non PIP2-interacting mutant D-hERG (with a deletion of the 883-894 amino acids) in the C-terminal and the non PKC-phosphorylable mutant N-terminal truncated-hERG (NTK-hERG) were transfected in HEK293 cells. Cell membranes were extracted by centrifugation and the different proteins were visualized by Western blot. Potassium currents were recorded by the patch-clamp technique. IKr was recorded in isolated feline cardiac myocytes. Results: Activation of the α1-AR reduces the amplitude of IhERG and IKr through a positive shift in the activation half voltage, which reduces the channel availability at physiological membrane potentials. The intracellular pathway connecting the α1-AR to the hERG channel in HEK293 cells includes activation of the Gαq protein, PLC activation and PIP2 hydrolysis, activation of PKC and direct phosphorylation of the hERG channel N-terminal. The PKC-mediated IKr channel phosphorylation and subsequent IKr reduction after α1-AR stimulation was corroborated in feline cardiac myocytes. Conclusions: These findings clarify the link between sympathetic nervous system hyperactivity and IKr reduction, one of the best characterized causes of torsades de pointes and ventricular fibrillation.
MeSH term(s)	Animals ; Cats ; Enzyme Activation/drug effects ; Ether-A-Go-Go Potassium Channels/metabolism ; HEK293 Cells ; Humans ; Ion Channel Gating/drug effects ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/enzymology ; Myocytes, Cardiac/metabolism ; Phenylephrine/pharmacology ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; Phosphorylation/drug effects ; Potassium Channels, Voltage-Gated/metabolism ; Protein Kinase C/metabolism ; Protein-Serine-Threonine Kinases/metabolism ; Receptors, Adrenergic, alpha-1/metabolism ; Signal Transduction/drug effects ; Type C Phospholipases/metabolism
Chemical Substances	Ether-A-Go-Go Potassium Channels ; KCNE2 protein, human ; KCNH1 protein, human ; Phosphatidylinositol 4,5-Diphosphate ; Potassium Channels, Voltage-Gated ; Receptors, Adrenergic, alpha-1 ; Phenylephrine (1WS297W6MV) ; MINK1 protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Protein Kinase C (EC 2.7.11.13) ; Type C Phospholipases (EC 3.1.4.-)
Language	English
Publishing date	2016-12-19
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.1159/000453180
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Zs.A 3160: Show issues

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Article ; Online: Mechanisms responsible for the trophic effect of beta-adrenoceptors on the I(to) current density in type 1 diabetic rat cardiomyocytes.

Setién, Raúl / Alday, Aintzane / Diaz-Asensio, Cristina / Urrutia, Janire / Gallego, Mónica / Casis, Oscar

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

2013 Volume 31, Issue 1, Page(s) 25–36

Abstract: Background/aims: In diabetic ventricular myocytes, transient outward potassium current (Ito) amplitude is severely reduced because of the impaired catecholamine release that characterizes diabetic autonomic neuropathy. Sympathetic nervous system ... ...

Abstract	Background/aims: In diabetic ventricular myocytes, transient outward potassium current (Ito) amplitude is severely reduced because of the impaired catecholamine release that characterizes diabetic autonomic neuropathy. Sympathetic nervous system exhibits a trophic effect on Ito since incubation of myocytes with noradrenaline restores current amplitude via beta-adrenoceptor (βAR) stimulation. Here, we investigate the intracellular signalling pathway though which incubation of diabetic cardiomyocytes with the βAR agonist isoproterenol recovers Ito amplitude to normal values. Methods: Experiments were performed in ventricular myocytes isolated from streptozotocin-diabetic rats. Ito current was recorded by using the patch-clamp technique. Kv4 channel expression was determined by immunofluorescence. Protein-protein interaction was determined by coimmunoprecipitation. Results: Stimulation of βAR activates first a Gαs protein, adenylyl cyclase and Protein Kinase A. PKA-phosphorylated receptor then switches to the Gαi protein. This leads to the activation of the βAR-Kinase-1 and further receptor phosphorylation and arrestin dependent internalization. The internalized receptor-arrestin complex recruits and activates cSrc and the MAPK cascade, where Ras, c-Raf1 and finally ERK1/2 mediate the increase in Kv4.2 and Kv4.3 protein abundance in the plasma membrane. Conclusion: β2AR stimulation activates a Gαs and Gαi protein dependent pathway where the ERK1/2 modulates the Ito current amplitude and the density of the Kv4.2 and Kv4.2 channels in the plasma membrane upon sympathetic stimulation in diabetic heart.
MeSH term(s)	Adenylyl Cyclases/metabolism ; Adrenergic beta-Agonists/pharmacology ; Animals ; Arrestin/metabolism ; Cells, Cultured ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; GTP-Binding Protein alpha Subunits, Gi-Go/metabolism ; GTP-Binding Protein alpha Subunits, Gs/metabolism ; Isoproterenol/pharmacology ; Membrane Potentials/drug effects ; Membrane Potentials/physiology ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Patch-Clamp Techniques ; Phosphorylation ; Potassium/metabolism ; Protein Interaction Maps/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta/chemistry ; Receptors, Adrenergic, beta/metabolism ; Shal Potassium Channels/metabolism ; Signal Transduction
Chemical Substances	Adrenergic beta-Agonists ; Arrestin ; Receptors, Adrenergic, beta ; Shal Potassium Channels ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; GTP-Binding Protein alpha Subunits, Gi-Go (EC 3.6.5.1) ; GTP-Binding Protein alpha Subunits, Gs (EC 3.6.5.1) ; Adenylyl Cyclases (EC 4.6.1.1) ; Isoproterenol (L628TT009W) ; Potassium (RWP5GA015D)
Language	English
Publishing date	2013-01-14
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.1159/000343346
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Mechanisms of I ; /I ; Modulation by α1-Adrenoceptors in HEK293 Cells and Cardiac Myocytes

Urrutia, Janire / Alday, Aintzane / Gallego, Mónica / Malagueta-Vieira, L. Layse / Aréchiga-Figueroa, Ivan Arael / Casis, Oscar / Sánchez-Chapula, José Antonio

Cellular Physiology and Biochemistry

2016 Volume 40, Issue 6, Page(s) 1261–1273

Abstract: Background: The rapid delayed rectifier K current (IKr), carried by the hERG protein, is one of the main repolarising currents in the human heart and a reduction of this current increases the risk of ventricular fibrillation. α1-adrenoceptors (α1-AR) ... ...

Institution	Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz Lascaray Research Centre, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain Unidad de Investigación “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, México
Abstract	Background: The rapid delayed rectifier K current (IKr), carried by the hERG protein, is one of the main repolarising currents in the human heart and a reduction of this current increases the risk of ventricular fibrillation. α1-adrenoceptors (α1-AR) activation reduces IKr but, despite the clear relationship between an increase in the sympathetic tone and arrhythmias, the mechanisms underlying the α1-AR regulation of the hERG channel are controversial. Thus, we aimed to investigate the mechanisms by which α1-AR stimulation regulates IKrMethods: α1-adrenoceptors, hERG channels, auxiliary subunits minK and MIRP1, the non PIP2-interacting mutant D-hERG (with a deletion of the 883-894 amino acids) in the C-terminal and the non PKC-phosphorylable mutant N-terminal truncated-hERG (NTK-hERG) were transfected in HEK293 cells. Cell membranes were extracted by centrifugation and the different proteins were visualized by Western blot. Potassium currents were recorded by the patch-clamp technique. IKr was recorded in isolated feline cardiac myocytes. Results: Activation of the α1-AR reduces the amplitude of IhERG and IKr through a positive shift in the activation half voltage, which reduces the channel availability at physiological membrane potentials. The intracellular pathway connecting the α1-AR to the hERG channel in HEK293 cells includes activation of the Gαq protein, PLC activation and PIP2 hydrolysis, activation of PKC and direct phosphorylation of the hERG channel N-terminal. The PKC-mediated IKr channel phosphorylation and subsequent IKr reduction after α1-AR stimulation was corroborated in feline cardiac myocytes. Conclusions: These findings clarify the link between sympathetic nervous system hyperactivity and IKr reduction, one of the best characterized causes of torsades de pointes and ventricular fibrillation.
Keywords	Phosphatidylinositol 4,5-bisphosphate ; Src ; PKA ; hERG ; PKC ; I
Language	English
Publishing date	2016-12-19
Publisher	S. Karger AG
Publishing place	Basel, Switzerland
Document type	Article
Note	Original Paper ; This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.1159/000453180
Database	Karger publisher's database

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