PittsburghV1, Main, Exploration, bibRecord, 001980

Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

Identifieur interne : 001980 ( Main/Exploration ); précédent : 001979; suivant : 001981

Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

Auteurs : Wei Xiong [États-Unis, République populaire de Chine] ; Shao-Rui Chen [États-Unis] ; Liming He [États-Unis] ; Kejun Cheng [États-Unis] ; Yi-Lin Zhao [États-Unis] ; Hong Chen [États-Unis] ; De-Pei Li [États-Unis] ; Gregg E. Homanics [États-Unis] ; John Peever [Canada] ; Kenner C. Rice [États-Unis] ; Ling-Gang Wu [États-Unis] ; Hui-Lin Pan [États-Unis] ; Li Zhang [États-Unis]

Source :

Nature neuroscience [ 1097-6256 ] ; 2014.

RBID : PMC:4019963

Descripteurs français

KwdFr :
- 6-Cyano-7-nitroquinoxaline-2,3-dion e (pharmacologie), Animaux, Antagonistes des acides aminés excitateurs (pharmacologie), Bloqueurs de canaux sodiques (pharmacologie), Cellules HEK293, Femelle, Humains, Modèles animaux de maladie humaine, Moelle spinale (cytologie), Mutants neurologiques de souris, Mutation (génétique), Mâle, Neurones (), Neurones (physiologie), Potentiels de membrane (), Potentiels de membrane (génétique), Potentiels de membrane (physiologie), Récepteur de la glycine (génétique), Récepteur de la glycine (métabolisme), Souris, Souris de lignée C57BL, Syndrome de l'homme raide (anatomopathologie), Syndrome de l'homme raide (génétique), Techniques in vitro, Terminaisons présynaptiques (), Terminaisons présynaptiques (métabolisme), Tronc cérébral (cytologie), Tétrodotoxine (pharmacologie), Valine (analogues et dérivés), Valine (pharmacologie).
MESH :
- analogues et dérivés : Valine.
- anatomopathologie : Syndrome de l'homme raide.
- cytologie : Moelle spinale, Tronc cérébral.
- génétique : Mutation, Potentiels de membrane, Récepteur de la glycine, Syndrome de l'homme raide.
- métabolisme : Récepteur de la glycine, Terminaisons présynaptiques.
- pharmacologie : 6-Cyano-7-nitroquinoxaline-2,3-dion e, Antagonistes des acides aminés excitateurs, Bloqueurs de canaux sodiques, Tétrodotoxine, Valine.
- physiologie : Neurones, Potentiels de membrane.
- Animaux, Cellules HEK293, Femelle, Humains, Modèles animaux de maladie humaine, Mutants neurologiques de souris, Mâle, Neurones, Potentiels de membrane, Souris, Souris de lignée C57BL, Techniques in vitro, Terminaisons présynaptiques.

English descriptors

KwdEn :
- 6-Cyano-7-nitroquinoxaline-2,3-dione (pharmacology), Animals, Brain Stem (cytology), Disease Models, Animal, Excitatory Amino Acid Antagonists (pharmacology), Female, HEK293 Cells, Humans, In Vitro Techniques, Male, Membrane Potentials (drug effects), Membrane Potentials (genetics), Membrane Potentials (physiology), Mice, Mice, Inbred C57BL, Mice, Neurologic Mutants, Mutation (genetics), Neurons (drug effects), Neurons (physiology), Presynaptic Terminals (drug effects), Presynaptic Terminals (metabolism), Receptors, Glycine (genetics), Receptors, Glycine (metabolism), Sodium Channel Blockers (pharmacology), Spinal Cord (cytology), Stiff-Person Syndrome (genetics), Stiff-Person Syndrome (pathology), Tetrodotoxin (pharmacology), Valine (analogs & derivatives), Valine (pharmacology).
MESH :
- chemical , analogs & derivatives : Valine.
- chemical , genetics : Receptors, Glycine.
- chemical , metabolism : Receptors, Glycine.
- chemical , pharmacology : 6-Cyano-7-nitroquinoxaline-2,3-dione, Excitatory Amino Acid Antagonists, Sodium Channel Blockers, Tetrodotoxin, Valine.
- cytology : Brain Stem, Spinal Cord.
- drug effects : Membrane Potentials, Neurons, Presynaptic Terminals.
- genetics : Membrane Potentials, Mutation, Stiff-Person Syndrome.
- metabolism : Presynaptic Terminals.
- pathology : Stiff-Person Syndrome.
- physiology : Membrane Potentials, Neurons.
- Animals, Disease Models, Animal, Female, HEK293 Cells, Humans, In Vitro Techniques, Male, Mice, Mice, Inbred C57BL, Mice, Neurologic Mutants.

Abstract

While postsynaptic GlyRs as α/β heteromers attract the most research attention, little is known about the role of presynaptic GlyRs, likely α homomers, in diseases. Here, we demonstrate that DH-CBD, a nonpsychoactive cannabinoid, can rescue GlyR functional deficiency and exaggerated acoustic and tactile startle responses in mice bearing the point-mutations in the α1 GlyRs responsible for a hereditary startle/hyperekplexia disease. The GlyRs expressed as α1 homomers either in HEK-293 cells or at presynaptic terminals of the calyceal synapses in auditory brainstem are most vulnerable to hyperekplexia mutation-induced impairment. Homomeric mutants are more sensitive than heteromers to DH-CBD, suggesting presynaptic GlyRs as a primary target. Consistent with this, DH-CBD selectively rescues impaired presynaptic GlyR activity and diminished glycine release in the brainstem and spinal cord of hyperekplexic mutant mice. Thus, presynaptic α GlyRs emerge as a potential therapeutic target for dominant hyperekplexia disease and other diseases with GlyR deficiency.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019963

DOI: 10.1038/nn.3615
PubMed: 24390226
PubMed Central: 4019963

Affiliations:

Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>6-Cyano-7-nitroquinoxaline-2,3-dione (pharmacology)</term>
<term>Animals</term>
<term>Brain Stem (cytology)</term>
<term>Disease Models, Animal</term>
<term>Excitatory Amino Acid Antagonists (pharmacology)</term>
<term>Female</term>
<term>HEK293 Cells</term>
<term>Humans</term>
<term>In Vitro Techniques</term>
<term>Male</term>
<term>Membrane Potentials (drug effects)</term>
<term>Membrane Potentials (genetics)</term>
<term>Membrane Potentials (physiology)</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Neurologic Mutants</term>
<term>Mutation (genetics)</term>
<term>Neurons (drug effects)</term>
<term>Neurons (physiology)</term>
<term>Presynaptic Terminals (drug effects)</term>
<term>Presynaptic Terminals (metabolism)</term>
<term>Receptors, Glycine (genetics)</term>
<term>Receptors, Glycine (metabolism)</term>
<term>Sodium Channel Blockers (pharmacology)</term>
<term>Spinal Cord (cytology)</term>
<term>Stiff-Person Syndrome (genetics)</term>
<term>Stiff-Person Syndrome (pathology)</term>
<term>Tetrodotoxin (pharmacology)</term>
<term>Valine (analogs & derivatives)</term>
<term>Valine (pharmacology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>6-Cyano-7-nitroquinoxaline-2,3-dion e (pharmacologie)</term>
<term>Animaux</term>
<term>Antagonistes des acides aminés excitateurs (pharmacologie)</term>
<term>Bloqueurs de canaux sodiques (pharmacologie)</term>
<term>Cellules HEK293</term>
<term>Femelle</term>
<term>Humains</term>
<term>Modèles animaux de maladie humaine</term>
<term>Moelle spinale (cytologie)</term>
<term>Mutants neurologiques de souris</term>
<term>Mutation (génétique)</term>
<term>Mâle</term>
<term>Neurones ()</term>
<term>Neurones (physiologie)</term>
<term>Potentiels de membrane ()</term>
<term>Potentiels de membrane (génétique)</term>
<term>Potentiels de membrane (physiologie)</term>
<term>Récepteur de la glycine (génétique)</term>
<term>Récepteur de la glycine (métabolisme)</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
<term>Syndrome de l'homme raide (anatomopathologie)</term>
<term>Syndrome de l'homme raide (génétique)</term>
<term>Techniques in vitro</term>
<term>Terminaisons présynaptiques ()</term>
<term>Terminaisons présynaptiques (métabolisme)</term>
<term>Tronc cérébral (cytologie)</term>
<term>Tétrodotoxine (pharmacologie)</term>
<term>Valine (analogues et dérivés)</term>
<term>Valine (pharmacologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Valine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Receptors, Glycine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Receptors, Glycine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>6-Cyano-7-nitroquinoxaline-2,3-dione</term>
<term>Excitatory Amino Acid Antagonists</term>
<term>Sodium Channel Blockers</term>
<term>Tetrodotoxin</term>
<term>Valine</term>
</keywords>
<keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Valine</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Syndrome de l'homme raide</term>
</keywords>
<keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Moelle spinale</term>
<term>Tronc cérébral</term>
</keywords>
<keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Brain Stem</term>
<term>Spinal Cord</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Membrane Potentials</term>
<term>Neurons</term>
<term>Presynaptic Terminals</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Membrane Potentials</term>
<term>Mutation</term>
<term>Stiff-Person Syndrome</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Mutation</term>
<term>Potentiels de membrane</term>
<term>Récepteur de la glycine</term>
<term>Syndrome de l'homme raide</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Presynaptic Terminals</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Récepteur de la glycine</term>
<term>Terminaisons présynaptiques</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Stiff-Person Syndrome</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>6-Cyano-7-nitroquinoxaline-2,3-dion e</term>
<term>Antagonistes des acides aminés excitateurs</term>
<term>Bloqueurs de canaux sodiques</term>
<term>Tétrodotoxine</term>
<term>Valine</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Neurones</term>
<term>Potentiels de membrane</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Membrane Potentials</term>
<term>Neurons</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Disease Models, Animal</term>
<term>Female</term>
<term>HEK293 Cells</term>
<term>Humans</term>
<term>In Vitro Techniques</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Neurologic Mutants</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Cellules HEK293</term>
<term>Femelle</term>
<term>Humains</term>
<term>Modèles animaux de maladie humaine</term>
<term>Mutants neurologiques de souris</term>
<term>Mâle</term>
<term>Neurones</term>
<term>Potentiels de membrane</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
<term>Techniques in vitro</term>
<term>Terminaisons présynaptiques</term>
</keywords>
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</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P1">While postsynaptic GlyRs as α/β heteromers attract the most research attention, little is known about the role of presynaptic GlyRs, likely α homomers, in diseases. Here, we demonstrate that DH-CBD, a nonpsychoactive cannabinoid, can rescue GlyR functional deficiency and exaggerated acoustic and tactile startle responses in mice bearing the point-mutations in the α1 GlyRs responsible for a hereditary startle/hyperekplexia disease. The GlyRs expressed as α1 homomers either in HEK-293 cells or at presynaptic terminals of the calyceal synapses in auditory brainstem are most vulnerable to hyperekplexia mutation-induced impairment. Homomeric mutants are more sensitive than heteromers to DH-CBD, suggesting presynaptic GlyRs as a primary target. Consistent with this, DH-CBD selectively rescues impaired presynaptic GlyR activity and diminished glycine release in the brainstem and spinal cord of hyperekplexic mutant mice. Thus, presynaptic α GlyRs emerge as a potential therapeutic target for dominant hyperekplexia disease and other diseases with GlyR deficiency.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Canada</li>
<li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
<region><li>Maryland</li>
<li>Ontario</li>
<li>Pennsylvanie</li>
<li>Texas</li>
</region>
<settlement><li>Toronto</li>
</settlement>
<orgName><li>Université de Toronto</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Maryland"><name sortKey="Xiong, Wei" sort="Xiong, Wei" uniqKey="Xiong W" first="Wei" last="Xiong">Wei Xiong</name>
</region>
<name sortKey="Chen, Hong" sort="Chen, Hong" uniqKey="Chen H" first="Hong" last="Chen">Hong Chen</name>
<name sortKey="Chen, Shao Rui" sort="Chen, Shao Rui" uniqKey="Chen S" first="Shao-Rui" last="Chen">Shao-Rui Chen</name>
<name sortKey="Cheng, Kejun" sort="Cheng, Kejun" uniqKey="Cheng K" first="Kejun" last="Cheng">Kejun Cheng</name>
<name sortKey="He, Liming" sort="He, Liming" uniqKey="He L" first="Liming" last="He">Liming He</name>
<name sortKey="Homanics, Gregg E" sort="Homanics, Gregg E" uniqKey="Homanics G" first="Gregg E." last="Homanics">Gregg E. Homanics</name>
<name sortKey="Li, De Pei" sort="Li, De Pei" uniqKey="Li D" first="De-Pei" last="Li">De-Pei Li</name>
<name sortKey="Pan, Hui Lin" sort="Pan, Hui Lin" uniqKey="Pan H" first="Hui-Lin" last="Pan">Hui-Lin Pan</name>
<name sortKey="Rice, Kenner C" sort="Rice, Kenner C" uniqKey="Rice K" first="Kenner C." last="Rice">Kenner C. Rice</name>
<name sortKey="Wu, Ling Gang" sort="Wu, Ling Gang" uniqKey="Wu L" first="Ling-Gang" last="Wu">Ling-Gang Wu</name>
<name sortKey="Zhang, Li" sort="Zhang, Li" uniqKey="Zhang L" first="Li" last="Zhang">Li Zhang</name>
<name sortKey="Zhao, Yi Lin" sort="Zhao, Yi Lin" uniqKey="Zhao Y" first="Yi-Lin" last="Zhao">Yi-Lin Zhao</name>
</country>
<country name="République populaire de Chine"><noRegion><name sortKey="Xiong, Wei" sort="Xiong, Wei" uniqKey="Xiong W" first="Wei" last="Xiong">Wei Xiong</name>
</noRegion>
</country>
<country name="Canada"><region name="Ontario"><name sortKey="Peever, John" sort="Peever, John" uniqKey="Peever J" first="John" last="Peever">John Peever</name>
</region>
</country>
</tree>
</affiliations>
</record>

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Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

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