TRPV1 variants impair intracellular Ca 2+ signaling and may confer susceptibility to malignant hyperthermia
Malignant hyperthermia (MH) is a pharmacogenetic disorder arising from uncontrolled muscle calcium release due to an abnormality in the sarcoplasmic reticulum (SR) calcium-release mechanism triggered by halogenated inhalational anesthetics. However, the molecular mechanisms involved are still incomp...
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| Veröffentlicht in: | Genetics in medicine 2019-02, Vol.21 (2), p.441 |
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| creator | Vanden Abeele, Fabien Lotteau, Sabine Ducreux, Sylvie Dubois, Charlotte Monnier, Nicole Hanna, Amy Gkika, Dimitra Romestaing, Caroline Noyer, Lucile Flourakis, Matthieu Tessier, Nolwenn Al-Mawla, Ribal Chouabe, Christophe Lefai, Etienne Lunardi, Joël Hamilton, Susan Fauré, Julien Van Coppenolle, Fabien Prevarskaya, Natalia |
| description | Malignant hyperthermia (MH) is a pharmacogenetic disorder arising from uncontrolled muscle calcium release due to an abnormality in the sarcoplasmic reticulum (SR) calcium-release mechanism triggered by halogenated inhalational anesthetics. However, the molecular mechanisms involved are still incomplete.
We aimed to identify transient receptor potential vanilloid 1 (TRPV1) variants within the entire coding sequence in patients who developed sensitivity to MH of unknown etiology. In vitro and in vivo functional studies were performed in heterologous expression system, trpv1
mice, and a murine model of human MH.
We identified TRPV1 variants in two patients and their heterologous expression in muscles of trpv1
mice strongly enhanced calcium release from SR upon halogenated anesthetic stimulation, suggesting they could be responsible for the MH phenotype. We confirmed the in vivo significance by using mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation associated with MH in humans. We showed that the TRPV1 antagonist capsazepine slows the heat-induced hypermetabolic response in this model.
We propose that TRPV1 contributes to MH and could represent an actionable therapeutic target for prevention of the pathology and also be responsible for MH sensitivity when mutated. |
| doi_str_mv | 10.1038/s41436-018-0066-9 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed</sourceid><recordid>TN_cdi_pubmed_primary_29930394</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>29930394</sourcerecordid><originalsourceid>FETCH-pubmed_primary_299303943</originalsourceid><addsrcrecordid>eNqFjsFKAzEQQIMgtrZ-gBeZu0QnmzV2z0XxWKR4LdNt2o4maZhkhf17FfTs6R3eOzylrg3eGbSL-9Ka1jqNZqERndPdmZqaB4sarXMTdVnKO6J5tA1eqEnTdRZt107Vx_p19Wbgk4Qp1QIcM7EApyrU-xCGQAJLguYWCh8SBU4HoLSDSCP0p7T3AmUovc-Vtxy4jlBP3zL8xKnCccxe6tFLZJqr8z2F4q9-OVM3z0_r5YvOwzb63SYLR5Jx83dn_w2-ACDaS7w</addsrcrecordid><sourcetype>Index Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>TRPV1 variants impair intracellular Ca 2+ signaling and may confer susceptibility to malignant hyperthermia</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>ProQuest Central UK/Ireland</source><source>Alma/SFX Local Collection</source><creator>Vanden Abeele, Fabien ; Lotteau, Sabine ; Ducreux, Sylvie ; Dubois, Charlotte ; Monnier, Nicole ; Hanna, Amy ; Gkika, Dimitra ; Romestaing, Caroline ; Noyer, Lucile ; Flourakis, Matthieu ; Tessier, Nolwenn ; Al-Mawla, Ribal ; Chouabe, Christophe ; Lefai, Etienne ; Lunardi, Joël ; Hamilton, Susan ; Fauré, Julien ; Van Coppenolle, Fabien ; Prevarskaya, Natalia</creator><creatorcontrib>Vanden Abeele, Fabien ; Lotteau, Sabine ; Ducreux, Sylvie ; Dubois, Charlotte ; Monnier, Nicole ; Hanna, Amy ; Gkika, Dimitra ; Romestaing, Caroline ; Noyer, Lucile ; Flourakis, Matthieu ; Tessier, Nolwenn ; Al-Mawla, Ribal ; Chouabe, Christophe ; Lefai, Etienne ; Lunardi, Joël ; Hamilton, Susan ; Fauré, Julien ; Van Coppenolle, Fabien ; Prevarskaya, Natalia</creatorcontrib><description>Malignant hyperthermia (MH) is a pharmacogenetic disorder arising from uncontrolled muscle calcium release due to an abnormality in the sarcoplasmic reticulum (SR) calcium-release mechanism triggered by halogenated inhalational anesthetics. However, the molecular mechanisms involved are still incomplete.
We aimed to identify transient receptor potential vanilloid 1 (TRPV1) variants within the entire coding sequence in patients who developed sensitivity to MH of unknown etiology. In vitro and in vivo functional studies were performed in heterologous expression system, trpv1
mice, and a murine model of human MH.
We identified TRPV1 variants in two patients and their heterologous expression in muscles of trpv1
mice strongly enhanced calcium release from SR upon halogenated anesthetic stimulation, suggesting they could be responsible for the MH phenotype. We confirmed the in vivo significance by using mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation associated with MH in humans. We showed that the TRPV1 antagonist capsazepine slows the heat-induced hypermetabolic response in this model.
We propose that TRPV1 contributes to MH and could represent an actionable therapeutic target for prevention of the pathology and also be responsible for MH sensitivity when mutated.</description><identifier>EISSN: 1530-0366</identifier><identifier>DOI: 10.1038/s41436-018-0066-9</identifier><identifier>PMID: 29930394</identifier><language>eng</language><publisher>United States</publisher><subject>Anesthetics - pharmacology ; Animals ; Calcium ; Calcium Signaling ; Disease Models, Animal ; Female ; Gene Expression - drug effects ; Gene Knock-In Techniques ; Genetic Predisposition to Disease ; HEK293 Cells ; Homeostasis ; Humans ; Male ; Malignant Hyperthermia - genetics ; Malignant Hyperthermia - metabolism ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal - metabolism ; TRPV Cation Channels - genetics ; TRPV Cation Channels - metabolism</subject><ispartof>Genetics in medicine, 2019-02, Vol.21 (2), p.441</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29930394$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vanden Abeele, Fabien</creatorcontrib><creatorcontrib>Lotteau, Sabine</creatorcontrib><creatorcontrib>Ducreux, Sylvie</creatorcontrib><creatorcontrib>Dubois, Charlotte</creatorcontrib><creatorcontrib>Monnier, Nicole</creatorcontrib><creatorcontrib>Hanna, Amy</creatorcontrib><creatorcontrib>Gkika, Dimitra</creatorcontrib><creatorcontrib>Romestaing, Caroline</creatorcontrib><creatorcontrib>Noyer, Lucile</creatorcontrib><creatorcontrib>Flourakis, Matthieu</creatorcontrib><creatorcontrib>Tessier, Nolwenn</creatorcontrib><creatorcontrib>Al-Mawla, Ribal</creatorcontrib><creatorcontrib>Chouabe, Christophe</creatorcontrib><creatorcontrib>Lefai, Etienne</creatorcontrib><creatorcontrib>Lunardi, Joël</creatorcontrib><creatorcontrib>Hamilton, Susan</creatorcontrib><creatorcontrib>Fauré, Julien</creatorcontrib><creatorcontrib>Van Coppenolle, Fabien</creatorcontrib><creatorcontrib>Prevarskaya, Natalia</creatorcontrib><title>TRPV1 variants impair intracellular Ca 2+ signaling and may confer susceptibility to malignant hyperthermia</title><title>Genetics in medicine</title><addtitle>Genet Med</addtitle><description>Malignant hyperthermia (MH) is a pharmacogenetic disorder arising from uncontrolled muscle calcium release due to an abnormality in the sarcoplasmic reticulum (SR) calcium-release mechanism triggered by halogenated inhalational anesthetics. However, the molecular mechanisms involved are still incomplete.
We aimed to identify transient receptor potential vanilloid 1 (TRPV1) variants within the entire coding sequence in patients who developed sensitivity to MH of unknown etiology. In vitro and in vivo functional studies were performed in heterologous expression system, trpv1
mice, and a murine model of human MH.
We identified TRPV1 variants in two patients and their heterologous expression in muscles of trpv1
mice strongly enhanced calcium release from SR upon halogenated anesthetic stimulation, suggesting they could be responsible for the MH phenotype. We confirmed the in vivo significance by using mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation associated with MH in humans. We showed that the TRPV1 antagonist capsazepine slows the heat-induced hypermetabolic response in this model.
We propose that TRPV1 contributes to MH and could represent an actionable therapeutic target for prevention of the pathology and also be responsible for MH sensitivity when mutated.</description><subject>Anesthetics - pharmacology</subject><subject>Animals</subject><subject>Calcium</subject><subject>Calcium Signaling</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Gene Expression - drug effects</subject><subject>Gene Knock-In Techniques</subject><subject>Genetic Predisposition to Disease</subject><subject>HEK293 Cells</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Male</subject><subject>Malignant Hyperthermia - genetics</subject><subject>Malignant Hyperthermia - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Muscle, Skeletal - metabolism</subject><subject>TRPV Cation Channels - genetics</subject><subject>TRPV Cation Channels - metabolism</subject><issn>1530-0366</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjsFKAzEQQIMgtrZ-gBeZu0QnmzV2z0XxWKR4LdNt2o4maZhkhf17FfTs6R3eOzylrg3eGbSL-9Ka1jqNZqERndPdmZqaB4sarXMTdVnKO6J5tA1eqEnTdRZt107Vx_p19Wbgk4Qp1QIcM7EApyrU-xCGQAJLguYWCh8SBU4HoLSDSCP0p7T3AmUovc-Vtxy4jlBP3zL8xKnCccxe6tFLZJqr8z2F4q9-OVM3z0_r5YvOwzb63SYLR5Jx83dn_w2-ACDaS7w</recordid><startdate>201902</startdate><enddate>201902</enddate><creator>Vanden Abeele, Fabien</creator><creator>Lotteau, Sabine</creator><creator>Ducreux, Sylvie</creator><creator>Dubois, Charlotte</creator><creator>Monnier, Nicole</creator><creator>Hanna, Amy</creator><creator>Gkika, Dimitra</creator><creator>Romestaing, Caroline</creator><creator>Noyer, Lucile</creator><creator>Flourakis, Matthieu</creator><creator>Tessier, Nolwenn</creator><creator>Al-Mawla, Ribal</creator><creator>Chouabe, Christophe</creator><creator>Lefai, Etienne</creator><creator>Lunardi, Joël</creator><creator>Hamilton, Susan</creator><creator>Fauré, Julien</creator><creator>Van Coppenolle, Fabien</creator><creator>Prevarskaya, Natalia</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>201902</creationdate><title>TRPV1 variants impair intracellular Ca 2+ signaling and may confer susceptibility to malignant hyperthermia</title><author>Vanden Abeele, Fabien ; 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However, the molecular mechanisms involved are still incomplete.
We aimed to identify transient receptor potential vanilloid 1 (TRPV1) variants within the entire coding sequence in patients who developed sensitivity to MH of unknown etiology. In vitro and in vivo functional studies were performed in heterologous expression system, trpv1
mice, and a murine model of human MH.
We identified TRPV1 variants in two patients and their heterologous expression in muscles of trpv1
mice strongly enhanced calcium release from SR upon halogenated anesthetic stimulation, suggesting they could be responsible for the MH phenotype. We confirmed the in vivo significance by using mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation associated with MH in humans. We showed that the TRPV1 antagonist capsazepine slows the heat-induced hypermetabolic response in this model.
We propose that TRPV1 contributes to MH and could represent an actionable therapeutic target for prevention of the pathology and also be responsible for MH sensitivity when mutated.</abstract><cop>United States</cop><pmid>29930394</pmid><doi>10.1038/s41436-018-0066-9</doi></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; ProQuest Central UK/Ireland; Alma/SFX Local Collection |
| subjects | Anesthetics - pharmacology Animals Calcium Calcium Signaling Disease Models, Animal Female Gene Expression - drug effects Gene Knock-In Techniques Genetic Predisposition to Disease HEK293 Cells Homeostasis Humans Male Malignant Hyperthermia - genetics Malignant Hyperthermia - metabolism Mice Mice, Inbred C57BL Muscle, Skeletal - metabolism TRPV Cation Channels - genetics TRPV Cation Channels - metabolism |
| title | TRPV1 variants impair intracellular Ca 2+ signaling and may confer susceptibility to malignant hyperthermia |
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