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Article: Functional consequences of the arrhythmogenic G306R KvLQT1 K+ channel mutant probed by viral gene transfer in cardiomyocytes

TitleFunctional consequences of the arrhythmogenic G306R KvLQT1 K+ channel mutant probed by viral gene transfer in cardiomyocytes
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2001
PublisherWiley-Blackwell Publishing Ltd.. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0022-3751
Citation
Journal Of Physiology, 2001, v. 533 n. 1, p. 127-133 How to Cite?
Abstract1. IKs, the slow component of the delayed rectifier potassium current, figures prominently in the repolarization of heart cells. The K+ channel gene KvLQT1 is mutated in the heritable long QT (LQT) syndrome. Heterologous coexpression of KvLQT1 and the accessory protein minK yields an IKs-like current. Nevertheless, the links between KvLQT1 and cardiac IKs are largely inferential. 2. Since the LQT syndrome mutant KvLQT1-G306R suppresses channel activity when coexpressed with wild-type KvLQT1 in a heterologous system, overexpression of this mutant in cardiomyocytes should reduce or eliminate native IKs if KvLQT1 is indeed the major molecular component of this current. To test this idea, we created the adenovirus AdRMGI-KvLQT1-G306R, which overexpress KvLQT1-G306R channels. 3. In > 60% of neonatal mouse myocytes, a sizable IKs could be measured using perforated-patch recordings (8.0 ± 1.6 pA pF-1, n = 13). IKs was increased by forskolin and blocked by clofilium or indapamide but not by E-4031. While cells infected with a reporter virus expressing only green fluorescent protein (GFP) displayed IKs similar to that in uninfected cells, AdRMGI-KvLQT1-G306R-infected cells showed a significantly reduced IKs (2.4 ± 1.1 pA pF-1, n = 10, P < 0.01) when measured 60-72 h after infection. Similar results were observed in adult guinea-pig myocytes (5.9 ± 1.2 pA pF-1, n = 9, for control vs. 0.1 ± 0.1 pA pF-1, n = 5, for AdRMGI-KvLQT1-G306R-infected cells). 4. We conclude that KvLQT1 is the major molecular component of IKs. Our results further establish a dominant-negative mechanism for the G306R LQT syndrome mutation.
Persistent Identifierhttp://hdl.handle.net/10722/91594
ISSN
2015 Impact Factor: 4.731
2015 SCImago Journal Rankings: 2.670
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLi, RAen_HK
dc.contributor.authorMiake, Jen_HK
dc.contributor.authorHoppe, UCen_HK
dc.contributor.authorJohns, DCen_HK
dc.contributor.authorMarbán, Een_HK
dc.contributor.authorBradley Nuss, Hen_HK
dc.date.accessioned2010-09-17T10:21:54Z-
dc.date.available2010-09-17T10:21:54Z-
dc.date.issued2001en_HK
dc.identifier.citationJournal Of Physiology, 2001, v. 533 n. 1, p. 127-133en_HK
dc.identifier.issn0022-3751en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91594-
dc.description.abstract1. IKs, the slow component of the delayed rectifier potassium current, figures prominently in the repolarization of heart cells. The K+ channel gene KvLQT1 is mutated in the heritable long QT (LQT) syndrome. Heterologous coexpression of KvLQT1 and the accessory protein minK yields an IKs-like current. Nevertheless, the links between KvLQT1 and cardiac IKs are largely inferential. 2. Since the LQT syndrome mutant KvLQT1-G306R suppresses channel activity when coexpressed with wild-type KvLQT1 in a heterologous system, overexpression of this mutant in cardiomyocytes should reduce or eliminate native IKs if KvLQT1 is indeed the major molecular component of this current. To test this idea, we created the adenovirus AdRMGI-KvLQT1-G306R, which overexpress KvLQT1-G306R channels. 3. In > 60% of neonatal mouse myocytes, a sizable IKs could be measured using perforated-patch recordings (8.0 ± 1.6 pA pF-1, n = 13). IKs was increased by forskolin and blocked by clofilium or indapamide but not by E-4031. While cells infected with a reporter virus expressing only green fluorescent protein (GFP) displayed IKs similar to that in uninfected cells, AdRMGI-KvLQT1-G306R-infected cells showed a significantly reduced IKs (2.4 ± 1.1 pA pF-1, n = 10, P < 0.01) when measured 60-72 h after infection. Similar results were observed in adult guinea-pig myocytes (5.9 ± 1.2 pA pF-1, n = 9, for control vs. 0.1 ± 0.1 pA pF-1, n = 5, for AdRMGI-KvLQT1-G306R-infected cells). 4. We conclude that KvLQT1 is the major molecular component of IKs. Our results further establish a dominant-negative mechanism for the G306R LQT syndrome mutation.en_HK
dc.languageengen_HK
dc.publisherWiley-Blackwell Publishing Ltd.. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0022-3751en_HK
dc.relation.ispartofJournal of Physiologyen_HK
dc.subjectChemicals And Cas Registry Numbersen_HK
dc.titleFunctional consequences of the arrhythmogenic G306R KvLQT1 K+ channel mutant probed by viral gene transfer in cardiomyocytesen_HK
dc.typeArticleen_HK
dc.identifier.emailLi, RA:ronaldli@hkucc.hku.hken_HK
dc.identifier.authorityLi, RA=rp01352en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1111/j.1469-7793.2001.0127b.xen_HK
dc.identifier.pmid11351021-
dc.identifier.pmcidPMC2278611-
dc.identifier.scopuseid_2-s2.0-0035866944en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0035866944&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume533en_HK
dc.identifier.issue1en_HK
dc.identifier.spage127en_HK
dc.identifier.epage133en_HK
dc.identifier.isiWOS:000168756800017-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK
dc.identifier.scopusauthoridMiake, J=35407176600en_HK
dc.identifier.scopusauthoridHoppe, UC=7101650810en_HK
dc.identifier.scopusauthoridJohns, DC=7201908632en_HK
dc.identifier.scopusauthoridMarbán, E=8075977300en_HK
dc.identifier.scopusauthoridBradley Nuss, H=19033613300en_HK

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