Complete reversal of Lambert–Eaton myasthenic syndrome synaptic impairment by the combined use of a K+ channel blocker and a Ca2+ channel agonist
Identifieur interne : 003751 ( Main/Exploration ); précédent : 003750; suivant : 003752Complete reversal of Lambert–Eaton myasthenic syndrome synaptic impairment by the combined use of a K+ channel blocker and a Ca2+ channel agonist
Auteurs : Tyler B. Tarr [États-Unis] ; David Lacomis [États-Unis] ; Stephen W. Reddel [Australie] ; Mary Liang [États-Unis] ; Guillermo Valdomir [États-Unis] ; Michael Frasso [États-Unis] ; Peter Wipf [États-Unis] ; Stephen D. Meriney [États-Unis]Source :
- The Journal of Physiology [ 0022-3751 ] ; 2014.
Descripteurs français
- KwdFr :
- 4-Amino-pyridine (analogues et dérivés), 4-Amino-pyridine (pharmacologie), Agonistes des canaux calciques (pharmacologie), Animaux, Femelle, Humains, Inhibiteurs des canaux potassiques (pharmacologie), Jonction neuromusculaire (), Jonction neuromusculaire (physiopathologie), Lignée cellulaire tumorale, Potentiels synaptiques, Purines (pharmacologie), Purines (usage thérapeutique), Souris, Syndrome myasthénique de Lambert-Eaton (métabolisme), Syndrome myasthénique de Lambert-Eaton (physiopathologie), Synergie des médicaments, Thiophènes (pharmacologie), Thiophènes (usage thérapeutique).
- MESH :
- analogues et dérivés : 4-Amino-pyridine.
- métabolisme : Syndrome myasthénique de Lambert-Eaton.
- pharmacologie : 4-Amino-pyridine, Agonistes des canaux calciques, Inhibiteurs des canaux potassiques, Purines, Thiophènes.
- physiopathologie : Jonction neuromusculaire, Syndrome myasthénique de Lambert-Eaton.
- usage thérapeutique : Purines, Thiophènes.
- Animaux, Femelle, Humains, Jonction neuromusculaire, Lignée cellulaire tumorale, Potentiels synaptiques, Souris, Synergie des médicaments.
English descriptors
- KwdEn :
- 4-Aminopyridine (analogs & derivatives), 4-Aminopyridine (pharmacology), Animals, Calcium Channel Agonists (pharmacology), Cell Line, Tumor, Drug Synergism, Female, Humans, Lambert-Eaton Myasthenic Syndrome (metabolism), Lambert-Eaton Myasthenic Syndrome (physiopathology), Mice, Neuromuscular Junction (drug effects), Neuromuscular Junction (physiopathology), Potassium Channel Blockers (pharmacology), Purines (pharmacology), Purines (therapeutic use), Synaptic Potentials, Thiophenes (pharmacology), Thiophenes (therapeutic use).
- MESH :
- chemical , analogs & derivatives : 4-Aminopyridine.
- chemical , pharmacology : 4-Aminopyridine, Calcium Channel Agonists, Potassium Channel Blockers, Purines, Thiophenes.
- drug effects : Neuromuscular Junction.
- metabolism : Lambert-Eaton Myasthenic Syndrome.
- physiopathology : Lambert-Eaton Myasthenic Syndrome, Neuromuscular Junction.
- chemical , therapeutic use : Purines, Thiophenes.
- Animals, Cell Line, Tumor, Drug Synergism, Female, Humans, Mice, Synaptic Potentials.
Abstract
Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disorder in which a significant fraction of the presynaptic P/Q-type Ca2+ channels critical to the triggering of neurotransmitter release at the neuromuscular junction (NMJ) are thought to be removed. There is no cure for LEMS, and the current most commonly used symptomatic treatment option is a potassium channel blocker [3,4-diaminopyridine (3,4-DAP)] that does not completely reverse symptoms and can have dose-limiting side-effects. We previously reported the development of a novel Ca2+ channel agonist, GV-58, as a possible alternative treatment strategy for LEMS. In this study, we tested the hypothesis that the combination of GV-58 and 3,4-DAP will elicit a supra-additive increase in neurotransmitter release at LEMS model NMJs. First, we tested GV-58 in a cell survival assay to assess potential effects on cyclin-dependent kinases (Cdks) and showed that GV-58 did not affect cell survival at the relevant concentrations for Ca2+ channel effects. Then, we examined the voltage dependence of GV-58 effects on Ca2+ channels using patch clamp techniques; this showed the effects of GV-58 to be dependent upon Ca2+ channel opening. Based on this mechanism, we predicted an interaction between 3,4-DAP and GV-58. We tested this hypothesis using a mouse passive transfer model of LEMS. Using intracellular electrophysiological
Url:
DOI: 10.1113/jphysiol.2014.276493
PubMed: 25015919
PubMed Central: 4229355
Affiliations:
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Tarr</name><affiliation wicri:level="2"><nlm:aff id="au1"><institution>Department of Neuroscience, Center for Neuroscience, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="au2"><institution>Center for the Neural Basis of Cognition, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Lacomis, David" sort="Lacomis, David" uniqKey="Lacomis D" first="David" last="Lacomis">David Lacomis</name><affiliation wicri:level="2"><nlm:aff id="au3"><institution>Division of Neuromuscular Diseases, Department of Neurology, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="au4"><institution>Department of Pathology, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Reddel, Stephen W" sort="Reddel, Stephen W" uniqKey="Reddel S" first="Stephen W" last="Reddel">Stephen W. Reddel</name><affiliation wicri:level="1"><nlm:aff id="au5"><institution>Department of Clinical Neurology, Concord Hospital</institution><addr-line>Sydney, NSW, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Sydney, NSW</wicri:regionArea><wicri:noRegion>NSW</wicri:noRegion></affiliation></author><author><name sortKey="Liang, Mary" sort="Liang, Mary" uniqKey="Liang M" first="Mary" last="Liang">Mary Liang</name><affiliation wicri:level="2"><nlm:aff id="au6"><institution>Department of Chemistry, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="au7"><institution>Center for Chemical Methodologies and Library Development, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Valdomir, Guillermo" sort="Valdomir, Guillermo" uniqKey="Valdomir G" first="Guillermo" last="Valdomir">Guillermo Valdomir</name><affiliation wicri:level="2"><nlm:aff id="au6"><institution>Department of Chemistry, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="au7"><institution>Center for Chemical Methodologies and Library Development, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Frasso, Michael" sort="Frasso, Michael" uniqKey="Frasso M" first="Michael" last="Frasso">Michael Frasso</name><affiliation wicri:level="2"><nlm:aff id="au6"><institution>Department of Chemistry, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="au7"><institution>Center for Chemical Methodologies and Library Development, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Wipf, Peter" sort="Wipf, Peter" uniqKey="Wipf P" first="Peter" last="Wipf">Peter Wipf</name><affiliation wicri:level="2"><nlm:aff id="au6"><institution>Department of Chemistry, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university" n="3">Université de Pittsburgh</orgName></affiliation><affiliation wicri:level="2"><nlm:aff id="au7"><institution>Center for Chemical Methodologies and Library Development, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university" n="3">Université de Pittsburgh</orgName></affiliation></author><author><name sortKey="Meriney, Stephen D" sort="Meriney, Stephen D" uniqKey="Meriney S" first="Stephen D" last="Meriney">Stephen D. Meriney</name><affiliation wicri:level="2"><nlm:aff id="au1"><institution>Department of Neuroscience, Center for Neuroscience, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="au2"><institution>Center for the Neural Basis of Cognition, University of Pittsburgh</institution><addr-line>Pittsburgh, PA, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pittsburgh, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of Physiology</title><idno type="ISSN">0022-3751</idno><idno type="eISSN">1469-7793</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>4-Aminopyridine (analogs & derivatives)</term><term>4-Aminopyridine (pharmacology)</term><term>Animals</term><term>Calcium Channel Agonists (pharmacology)</term><term>Cell Line, Tumor</term><term>Drug Synergism</term><term>Female</term><term>Humans</term><term>Lambert-Eaton Myasthenic Syndrome (metabolism)</term><term>Lambert-Eaton Myasthenic Syndrome (physiopathology)</term><term>Mice</term><term>Neuromuscular Junction (drug effects)</term><term>Neuromuscular Junction (physiopathology)</term><term>Potassium Channel Blockers (pharmacology)</term><term>Purines (pharmacology)</term><term>Purines (therapeutic use)</term><term>Synaptic Potentials</term><term>Thiophenes (pharmacology)</term><term>Thiophenes (therapeutic use)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>4-Amino-pyridine (analogues et dérivés)</term><term>4-Amino-pyridine (pharmacologie)</term><term>Agonistes des canaux calciques (pharmacologie)</term><term>Animaux</term><term>Femelle</term><term>Humains</term><term>Inhibiteurs des canaux potassiques (pharmacologie)</term><term>Jonction neuromusculaire ()</term><term>Jonction neuromusculaire (physiopathologie)</term><term>Lignée cellulaire tumorale</term><term>Potentiels synaptiques</term><term>Purines (pharmacologie)</term><term>Purines (usage thérapeutique)</term><term>Souris</term><term>Syndrome myasthénique de Lambert-Eaton (métabolisme)</term><term>Syndrome myasthénique de Lambert-Eaton (physiopathologie)</term><term>Synergie des médicaments</term><term>Thiophènes (pharmacologie)</term><term>Thiophènes (usage thérapeutique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>4-Aminopyridine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>4-Aminopyridine</term><term>Calcium Channel Agonists</term><term>Potassium Channel Blockers</term><term>Purines</term><term>Thiophenes</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>4-Amino-pyridine</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Neuromuscular Junction</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lambert-Eaton Myasthenic Syndrome</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Syndrome myasthénique de Lambert-Eaton</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>4-Amino-pyridine</term><term>Agonistes des canaux calciques</term><term>Inhibiteurs des canaux potassiques</term><term>Purines</term><term>Thiophènes</term></keywords><keywords scheme="MESH" qualifier="physiopathologie" xml:lang="fr"><term>Jonction neuromusculaire</term><term>Syndrome myasthénique de Lambert-Eaton</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Lambert-Eaton Myasthenic Syndrome</term><term>Neuromuscular Junction</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Purines</term><term>Thiophenes</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Purines</term><term>Thiophènes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Drug Synergism</term><term>Female</term><term>Humans</term><term>Mice</term><term>Synaptic Potentials</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Femelle</term><term>Humains</term><term>Jonction neuromusculaire</term><term>Lignée cellulaire tumorale</term><term>Potentiels synaptiques</term><term>Souris</term><term>Synergie des médicaments</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disorder in which a significant fraction of the presynaptic P/Q-type Ca<sup>2+</sup> channels critical to the triggering of neurotransmitter release at the neuromuscular junction (NMJ) are thought to be removed. There is no cure for LEMS, and the current most commonly used symptomatic treatment option is a potassium channel blocker [3,4-diaminopyridine (3,4-DAP)] that does not completely reverse symptoms and can have dose-limiting side-effects. We previously reported the development of a novel Ca<sup>2+</sup> channel agonist, GV-58, as a possible alternative treatment strategy for LEMS. In this study, we tested the hypothesis that the combination of GV-58 and 3,4-DAP will elicit a supra-additive increase in neurotransmitter release at LEMS model NMJs. First, we tested GV-58 in a cell survival assay to assess potential effects on cyclin-dependent kinases (Cdks) and showed that GV-58 did not affect cell survival at the relevant concentrations for Ca<sup>2+</sup> channel effects. Then, we examined the voltage dependence of GV-58 effects on Ca<sup>2+</sup> channels using patch clamp techniques; this showed the effects of GV-58 to be dependent upon Ca<sup>2+</sup> channel opening. Based on this mechanism, we predicted an interaction between 3,4-DAP and GV-58. We tested this hypothesis using a mouse passive transfer model of LEMS. Using intracellular electrophysiological <italic>ex vivo</italic> recordings, we demonstrated that a combined application of 3,4-DAP plus GV-58 had a supra-additive effect that completely reversed the deficit in neurotransmitter release magnitude at LEMS model NMJs. This reversal contrasts with the less significant improvement observed with either compound alone. Our data indicate that a combination of 3,4-DAP and GV-58 represents a promising treatment option for LEMS and potentially for other disorders of the NMJ.</p></div></front></TEI><affiliations><list><country><li>Australie</li><li>États-Unis</li></country><region><li>Pennsylvanie</li></region><settlement><li>Pittsburgh</li></settlement><orgName><li>Université de Pittsburgh</li></orgName></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Tarr, Tyler B" sort="Tarr, Tyler B" uniqKey="Tarr T" first="Tyler B" last="Tarr">Tyler B. Tarr</name></region><name sortKey="Frasso, Michael" sort="Frasso, Michael" uniqKey="Frasso M" first="Michael" last="Frasso">Michael Frasso</name><name sortKey="Frasso, Michael" sort="Frasso, Michael" uniqKey="Frasso M" first="Michael" last="Frasso">Michael Frasso</name><name sortKey="Lacomis, David" sort="Lacomis, David" uniqKey="Lacomis D" first="David" last="Lacomis">David Lacomis</name><name sortKey="Lacomis, David" sort="Lacomis, David" uniqKey="Lacomis D" first="David" last="Lacomis">David Lacomis</name><name sortKey="Liang, Mary" sort="Liang, Mary" uniqKey="Liang M" first="Mary" last="Liang">Mary Liang</name><name sortKey="Liang, Mary" sort="Liang, Mary" uniqKey="Liang M" first="Mary" last="Liang">Mary Liang</name><name sortKey="Meriney, Stephen D" sort="Meriney, Stephen D" uniqKey="Meriney S" first="Stephen D" last="Meriney">Stephen D. Meriney</name><name sortKey="Meriney, Stephen D" sort="Meriney, Stephen D" uniqKey="Meriney S" first="Stephen D" last="Meriney">Stephen D. Meriney</name><name sortKey="Tarr, Tyler B" sort="Tarr, Tyler B" uniqKey="Tarr T" first="Tyler B" last="Tarr">Tyler B. Tarr</name><name sortKey="Valdomir, Guillermo" sort="Valdomir, Guillermo" uniqKey="Valdomir G" first="Guillermo" last="Valdomir">Guillermo Valdomir</name><name sortKey="Valdomir, Guillermo" sort="Valdomir, Guillermo" uniqKey="Valdomir G" first="Guillermo" last="Valdomir">Guillermo Valdomir</name><name sortKey="Wipf, Peter" sort="Wipf, Peter" uniqKey="Wipf P" first="Peter" last="Wipf">Peter Wipf</name><name sortKey="Wipf, Peter" sort="Wipf, Peter" uniqKey="Wipf P" first="Peter" last="Wipf">Peter Wipf</name></country><country name="Australie"><noRegion><name sortKey="Reddel, Stephen W" sort="Reddel, Stephen W" uniqKey="Reddel S" first="Stephen W" last="Reddel">Stephen W. Reddel</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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