Subthreshold changes of voltage-dependent activation of the KV7.2 channel in neonatal epilepsy
Benign familial neonatal convulsions (BFNC) is an epileptic disorder caused by dominant mutations in the genes KCNQ2 and KCNQ3 encoding the K+ channels KV7.2 and KV7.3. We identified two novel KCNQ2 mutations in two BFNC families. One mutation predicted a truncated protein (S247X) that lacks the cha...
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2006-10-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996106001495 |
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doaj-9a7c9e9c882c455683e37d85302ffdb12021-03-20T04:53:11ZengElsevierNeurobiology of Disease1095-953X2006-10-01241194201Subthreshold changes of voltage-dependent activation of the KV7.2 channel in neonatal epilepsyJessica Hunter0Snezana Maljevic1Anupama Shankar2Anne Siegel3Barbara Weissman4Philip Holt5Larry Olson6Holger Lerche7Andrew Escayg8Department of Human Genetics, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, Georgia 30322, USADepartments of Neurology and Applied Physiology, University of Ulm, Zentrum Klinische Forschung, Helmholtzstr. 8/1 D-89081 Ulm, GermanyDepartment of Human Genetics, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, Georgia 30322, USADepartment of Human Genetics, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, Georgia 30322, USADepartment of Neurology, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, Georgia 30322, USADepartment of Neurology, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, Georgia 30322, USADepartment of Neurology, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, Georgia 30322, USADepartments of Neurology and Applied Physiology, University of Ulm, Zentrum Klinische Forschung, Helmholtzstr. 8/1 D-89081 Ulm, Germany; Corresponding authors. A. Escayg is to be contacted at fax: +1 404 727 3949. H. Lerche, fax: +49 731 177 1202.Department of Human Genetics, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, Georgia 30322, USA; Corresponding authors. A. Escayg is to be contacted at fax: +1 404 727 3949. H. Lerche, fax: +49 731 177 1202.Benign familial neonatal convulsions (BFNC) is an epileptic disorder caused by dominant mutations in the genes KCNQ2 and KCNQ3 encoding the K+ channels KV7.2 and KV7.3. We identified two novel KCNQ2 mutations in two BFNC families. One mutation predicted a truncated protein (S247X) that lacks the channel's pore region, the other resulted in the amino acid substitution S122L in the S2 segment of KV7.2. In comparison to wild-type (WT) KV7.2, functional analysis of S122L mutant channels in Xenopus oocytes revealed a significant positive shift and increased slope of the activation curve leading to significant current reduction in the subthreshold range of an action potential (75% reduction at −50 mV). Our results establish an important role of the KV7.2 S2 segment in voltage-dependent channel gating and demonstrate in a human disease that subthreshold voltages are likely to represent the physiologically relevant range for this K+ channel to regulate neuronal firing.http://www.sciencedirect.com/science/article/pii/S0969996106001495BFNCEpilepsyIon channelGeneticsStructure function analysisVoltage clamp |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Jessica Hunter Snezana Maljevic Anupama Shankar Anne Siegel Barbara Weissman Philip Holt Larry Olson Holger Lerche Andrew Escayg |
| spellingShingle |
Jessica Hunter Snezana Maljevic Anupama Shankar Anne Siegel Barbara Weissman Philip Holt Larry Olson Holger Lerche Andrew Escayg Subthreshold changes of voltage-dependent activation of the KV7.2 channel in neonatal epilepsy Neurobiology of Disease BFNC Epilepsy Ion channel Genetics Structure function analysis Voltage clamp |
| author_facet |
Jessica Hunter Snezana Maljevic Anupama Shankar Anne Siegel Barbara Weissman Philip Holt Larry Olson Holger Lerche Andrew Escayg |
| author_sort |
Jessica Hunter |
| title |
Subthreshold changes of voltage-dependent activation of the KV7.2 channel in neonatal epilepsy |
| title_short |
Subthreshold changes of voltage-dependent activation of the KV7.2 channel in neonatal epilepsy |
| title_full |
Subthreshold changes of voltage-dependent activation of the KV7.2 channel in neonatal epilepsy |
| title_fullStr |
Subthreshold changes of voltage-dependent activation of the KV7.2 channel in neonatal epilepsy |
| title_full_unstemmed |
Subthreshold changes of voltage-dependent activation of the KV7.2 channel in neonatal epilepsy |
| title_sort |
subthreshold changes of voltage-dependent activation of the kv7.2 channel in neonatal epilepsy |
| publisher |
Elsevier |
| series |
Neurobiology of Disease |
| issn |
1095-953X |
| publishDate |
2006-10-01 |
| description |
Benign familial neonatal convulsions (BFNC) is an epileptic disorder caused by dominant mutations in the genes KCNQ2 and KCNQ3 encoding the K+ channels KV7.2 and KV7.3. We identified two novel KCNQ2 mutations in two BFNC families. One mutation predicted a truncated protein (S247X) that lacks the channel's pore region, the other resulted in the amino acid substitution S122L in the S2 segment of KV7.2. In comparison to wild-type (WT) KV7.2, functional analysis of S122L mutant channels in Xenopus oocytes revealed a significant positive shift and increased slope of the activation curve leading to significant current reduction in the subthreshold range of an action potential (75% reduction at −50 mV). Our results establish an important role of the KV7.2 S2 segment in voltage-dependent channel gating and demonstrate in a human disease that subthreshold voltages are likely to represent the physiologically relevant range for this K+ channel to regulate neuronal firing. |
| topic |
BFNC Epilepsy Ion channel Genetics Structure function analysis Voltage clamp |
| url |
http://www.sciencedirect.com/science/article/pii/S0969996106001495 |
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