Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/37889
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dc.contributor.authorMitcheson, John S.-
dc.contributor.authorChen, J-
dc.contributor.authorSanguinetti, Michael C.-
dc.date.accessioned2016-08-01T12:44:24Z-
dc.date.available2016-08-01T12:44:24Z-
dc.date.issued2000-02-14-
dc.identifier.citationJournal of General Physiology, 2000, 115 (3), pp. 229-240en
dc.identifier.issn0022-1295-
dc.identifier.urihttp://jgp.rupress.org/content/115/3/229.abstracten
dc.identifier.urihttp://hdl.handle.net/2381/37889-
dc.description.abstractDeactivation of voltage-gated potassium (K⁺) channels can slow or prevent the recovery from block by charged organic compounds, a phenomenon attributed to trapping of the compound within the inner vestibule by closure of the activation gate. Unbinding and exit from the channel vestibule of a positively charged organic compound should be favored by membrane hyperpolarization if not impeded by the closed gate. MK-499, a methanesulfonanilide compound, is a potent blocker (IC₅₀ = 32 nM) of HERG K⁺ channels. This bulky compound (7 × 20 Å) is positively charged at physiological pH. Recovery from block of HERG channels by MK-499 and other methanesulfonanilides is extremely slow (Carmeliet 1992; Ficker et al. 1998), suggesting a trapping mechanism. We used a mutant HERG (D540K) channel expressed in Xenopus oocytes to test the trapping hypothesis. D540K HERG has the unusual property of opening in response to hyperpolarization, in addition to relatively normal gating and channel opening in response to depolarization (Sanguinetti and Xu 1999). The hyperpolarization-activated state of HERG was characterized by long bursts of single channel reopening. Channel reopening allowed recovery from block by 2 μM MK-499 to occur with time constants of 10.5 and 52.7 s at −160 mV. In contrast, wild-type HERG channels opened only briefly after membrane hyperpolarization, and thus did not permit recovery from block by MK-499. These findings provide direct evidence that the mechanism of slow recovery from HERG channel block by methanesulfonanilides is due to trapping of the compound in the inner vestibule by closure of the activation gate. The ability of HERG channels to trap MK-499, despite its large size, suggests that the vestibule of this channel is larger than the well studied Shaker K⁺ channel.en
dc.language.isoenen
dc.publisherRockefeller University Pressen
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pubmed/10694252-
dc.rightsCopyright © 2000, the author(s). Deposited with reference to the publisher’s archiving policy available on the SHERPA/RoMEO website.en
dc.subjectAnimalsen
dc.subjectAnti-Arrhythmia Agentsen
dc.subjectBenzopyransen
dc.subjectCation Transport Proteinsen
dc.subjectDose-Response Relationship, Drugen
dc.subjectEther-A-Go-Go Potassium Channelsen
dc.subjectIon Channel Gatingen
dc.subjectMembrane Potentialsen
dc.subjectMutation, Missenseen
dc.subjectOocytesen
dc.subjectPatch-Clamp Techniquesen
dc.subjectPiperidinesen
dc.subjectPotassium Channelsen
dc.subjectPotassium Channels, Voltage-Gateden
dc.subjectXenopusen
dc.titleTrapping of a Methanesulfonanilide by Closure of the Herg Potassium Channel Activation Gateen
dc.typeJournal Articleen
dc.identifier.doi10.1085/jgp.115.3.229-
dc.identifier.eissn1540-7748-
dc.description.statusPeer-revieweden
dc.description.versionPublisher Versionen
dc.type.subtypeJournal Article;Research Support, Non-U.S. Gov't;Research Support, U.S. Gov't, P.H.S.-
pubs.organisational-group/Organisationen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGYen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departmentsen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biologyen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themesen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themes/Canceren
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themes/Cardiovascularen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themes/Molecular & Cellular Bioscienceen
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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