PubMed:10772658 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/10772658","sourcedb":"PubMed","sourceid":"10772658","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/10772658","text":"A revised view of cardiac sodium channel \"blockade\" in the long-QT syndrome.\nMutations in SCN5A, encoding the cardiac sodium (Na) channel, are linked to a form of the congenital long-QT syndrome (LQT3) that provokes lethal ventricular arrhythmias. These autosomal dominant mutations disrupt Na channel function, inhibiting channel inactivation, thereby causing a sustained ionic current that delays cardiac repolarization. Sodium channel-blocking antiarrhythmics, such as lidocaine, potently inhibit this pathologic Na current (I(Na)) and are being evaluated in patients with LQT3. The mechanism underlying this effect is unknown, although high-affinity \"block\" of the open Na channel pore has been proposed. Here we report that a recently identified LQT3 mutation (R1623Q) imparts unusual lidocaine sensitivity to the Na channel that is attributable to its altered functional behavior. Studies of lidocaine on individual R1623Q single-channel openings indicate that the open-time distribution is not changed, indicating the drug does not block the open pore as proposed previously. Rather, the mutant channels have a propensity to inactivate without ever opening (\"closed-state inactivation\"), and lidocaine augments this gating behavior. An allosteric gating model incorporating closed-state inactivation recapitulates the effects of lidocaine on pathologic I(Na). These findings explain the unusual drug sensitivity of R1623Q and provide a general and unanticipated mechanism for understanding how Na channel-blocking agents may suppress the pathologic, sustained Na current induced by LQT3 mutations.","tracks":[{"project":"PubmedHPO","denotations":[{"id":"T1","span":{"begin":178,"end":194},"obj":"HP_0001657"},{"id":"T2","span":{"begin":223,"end":246},"obj":"HP_0004308"},{"id":"T3","span":{"begin":235,"end":246},"obj":"HP_0011675"},{"id":"T4","span":{"begin":254,"end":272},"obj":"HP_0000006"}],"attributes":[{"subj":"T1","pred":"source","obj":"PubmedHPO"},{"subj":"T2","pred":"source","obj":"PubmedHPO"},{"subj":"T3","pred":"source","obj":"PubmedHPO"},{"subj":"T4","pred":"source","obj":"PubmedHPO"}]},{"project":"DisGeNET5_variant_disease","denotations":[{"id":"10772658-9#55#61#geners137854600","span":{"begin":1422,"end":1428},"obj":"geners137854600"},{"id":"10772658-9#222#226#diseaseC1859062","span":{"begin":1589,"end":1593},"obj":"diseaseC1859062"}],"relations":[{"id":"55#61#geners137854600222#226#diseaseC1859062","pred":"associated_with","subj":"10772658-9#55#61#geners137854600","obj":"10772658-9#222#226#diseaseC1859062"}],"attributes":[{"subj":"10772658-9#55#61#geners137854600","pred":"source","obj":"DisGeNET5_variant_disease"},{"subj":"10772658-9#222#226#diseaseC1859062","pred":"source","obj":"DisGeNET5_variant_disease"}]},{"project":"DisGeNET5_gene_disease","denotations":[{"id":"10772658-1#13#18#gene6331","span":{"begin":90,"end":95},"obj":"gene6331"},{"id":"10772658-1#90#117#diseaseC1141890","span":{"begin":167,"end":194},"obj":"diseaseC1141890"},{"id":"10772658-1#119#123#diseaseC1859062","span":{"begin":196,"end":200},"obj":"diseaseC1859062"},{"id":"10772658-1#146#169#diseaseC0085612","span":{"begin":223,"end":246},"obj":"diseaseC0085612"}],"relations":[{"id":"13#18#gene633190#117#diseaseC1141890","pred":"associated_with","subj":"10772658-1#13#18#gene6331","obj":"10772658-1#90#117#diseaseC1141890"},{"id":"13#18#gene6331119#123#diseaseC1859062","pred":"associated_with","subj":"10772658-1#13#18#gene6331","obj":"10772658-1#119#123#diseaseC1859062"},{"id":"13#18#gene6331146#169#diseaseC0085612","pred":"associated_with","subj":"10772658-1#13#18#gene6331","obj":"10772658-1#146#169#diseaseC0085612"}],"attributes":[{"subj":"10772658-1#13#18#gene6331","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"10772658-1#90#117#diseaseC1141890","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"10772658-1#119#123#diseaseC1859062","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"10772658-1#146#169#diseaseC0085612","pred":"source","obj":"DisGeNET5_gene_disease"}]},{"project":"PMID_GLOBAL","denotations":[{"id":"T1","span":{"begin":59,"end":75},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":167,"end":194},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":196,"end":200},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T4","span":{"begin":576,"end":580},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T5","span":{"begin":751,"end":755},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T6","span":{"begin":800,"end":811},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T7","span":{"begin":1151,"end":1155},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T8","span":{"begin":1407,"end":1418},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T9","span":{"begin":1589,"end":1593},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"0002442"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"0019171"},{"id":"A3","pred":"mondo_id","subj":"T3","obj":"0011377"},{"id":"A4","pred":"mondo_id","subj":"T4","obj":"0011377"},{"id":"A5","pred":"mondo_id","subj":"T5","obj":"0011377"},{"id":"A6","pred":"mondo_id","subj":"T6","obj":"0000605"},{"id":"A7","pred":"mondo_id","subj":"T7","obj":"0009176"},{"id":"A8","pred":"mondo_id","subj":"T8","obj":"0000605"},{"id":"A9","pred":"mondo_id","subj":"T9","obj":"0011377"},{"subj":"T1","pred":"source","obj":"PMID_GLOBAL"},{"subj":"T2","pred":"source","obj":"PMID_GLOBAL"},{"subj":"T3","pred":"source","obj":"PMID_GLOBAL"},{"subj":"T4","pred":"source","obj":"PMID_GLOBAL"},{"subj":"T5","pred":"source","obj":"PMID_GLOBAL"},{"subj":"T6","pred":"source","obj":"PMID_GLOBAL"},{"subj":"T7","pred":"source","obj":"PMID_GLOBAL"},{"subj":"T8","pred":"source","obj":"PMID_GLOBAL"},{"subj":"T9","pred":"source","obj":"PMID_GLOBAL"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"PubmedHPO","color":"#93ecc2","default":true},{"id":"DisGeNET5_variant_disease","color":"#eca893"},{"id":"DisGeNET5_gene_disease","color":"#9398ec"},{"id":"PMID_GLOBAL","color":"#b2ec93"}]}]}}