Compromised function in the Nav1.2 Dravet syndrome mutation R1312T
Ion channels, specifically voltage-gated sodium channels (Navs), are common culprits in inheritable seizure disorders. Some Nav isoforms are particularly susceptible, while others are only weakly associated with neuronal hyperexcitability. Representative of the latter group is Nav1.2 (gene name SCN2...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2012-09-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996112002033 |
| _version_ | 1818620446002642944 |
|---|---|
| author | Christoph Lossin Xiuyu Shi Michael A. Rogawski Shinichi Hirose |
| author_facet | Christoph Lossin Xiuyu Shi Michael A. Rogawski Shinichi Hirose |
| author_sort | Christoph Lossin |
| collection | DOAJ |
| description | Ion channels, specifically voltage-gated sodium channels (Navs), are common culprits in inheritable seizure disorders. Some Nav isoforms are particularly susceptible, while others are only weakly associated with neuronal hyperexcitability. Representative of the latter group is Nav1.2 (gene name SCN2A): despite its abundance in the brain, Nav1.2-related epilepsy is rare and only few studies have been conducted as to the pathophysiological basis of Nav1.2 in neuronal hyperexcitability. We here present a detailed functional analysis of Nav1.2 mutant, R1312T, which was originally found in a child with Dravet syndrome (formerly known as severe myoclonic epilepsy of infancy or SMEI). Whole-cell voltage clamp analysis revealed clearly compromised function: the mutant channels fast- and slow-inactivated at markedly more negative potentials and recovered from fast inactivation more slowly, which resulted in a use-dependent current reduction to less than 50% of wildtype levels. We also noted a small hyperpolarizing shift in the voltage dependence of activation. Our findings expand the spectrum of abnormal Nav channel behavior in epilepsy and raise the question as to how loss-of-function in a sodium channel predominantly expressed in excitatory neurons can lead to hyperexcitability. |
| first_indexed | 2024-12-16T17:53:30Z |
| format | Article |
| id | doaj.art-20982a824d5543f79a62509893e271f3 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T17:53:30Z |
| publishDate | 2012-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-20982a824d5543f79a62509893e271f32022-12-21T22:22:14ZengElsevierNeurobiology of Disease1095-953X2012-09-01473378384Compromised function in the Nav1.2 Dravet syndrome mutation R1312TChristoph Lossin0Xiuyu Shi1Michael A. Rogawski2Shinichi Hirose3Department of Neurology, University of California, Davis, School of Medicine, USA; Corresponding author at: 4635 Second Ave, Room 1004A, Sacramento, CA 95817, USA. Fax: +1 916 703 5512.Department of Pediatrics, Fukuoka University, Japan; Department of Pediatrics, Chinese PLA General Hospital, Beijing, ChinaDepartment of Neurology, University of California, Davis, School of Medicine, USADepartment of Pediatrics, Fukuoka University, JapanIon channels, specifically voltage-gated sodium channels (Navs), are common culprits in inheritable seizure disorders. Some Nav isoforms are particularly susceptible, while others are only weakly associated with neuronal hyperexcitability. Representative of the latter group is Nav1.2 (gene name SCN2A): despite its abundance in the brain, Nav1.2-related epilepsy is rare and only few studies have been conducted as to the pathophysiological basis of Nav1.2 in neuronal hyperexcitability. We here present a detailed functional analysis of Nav1.2 mutant, R1312T, which was originally found in a child with Dravet syndrome (formerly known as severe myoclonic epilepsy of infancy or SMEI). Whole-cell voltage clamp analysis revealed clearly compromised function: the mutant channels fast- and slow-inactivated at markedly more negative potentials and recovered from fast inactivation more slowly, which resulted in a use-dependent current reduction to less than 50% of wildtype levels. We also noted a small hyperpolarizing shift in the voltage dependence of activation. Our findings expand the spectrum of abnormal Nav channel behavior in epilepsy and raise the question as to how loss-of-function in a sodium channel predominantly expressed in excitatory neurons can lead to hyperexcitability.http://www.sciencedirect.com/science/article/pii/S0969996112002033Nav1.2SCN2AMutationEpilepsyDravet syndromeElectrophysiology |
| spellingShingle | Christoph Lossin Xiuyu Shi Michael A. Rogawski Shinichi Hirose Compromised function in the Nav1.2 Dravet syndrome mutation R1312T Neurobiology of Disease Nav1.2 SCN2A Mutation Epilepsy Dravet syndrome Electrophysiology |
| title | Compromised function in the Nav1.2 Dravet syndrome mutation R1312T |
| title_full | Compromised function in the Nav1.2 Dravet syndrome mutation R1312T |
| title_fullStr | Compromised function in the Nav1.2 Dravet syndrome mutation R1312T |
| title_full_unstemmed | Compromised function in the Nav1.2 Dravet syndrome mutation R1312T |
| title_short | Compromised function in the Nav1.2 Dravet syndrome mutation R1312T |
| title_sort | compromised function in the nav1 2 dravet syndrome mutation r1312t |
| topic | Nav1.2 SCN2A Mutation Epilepsy Dravet syndrome Electrophysiology |
| url | http://www.sciencedirect.com/science/article/pii/S0969996112002033 |
| work_keys_str_mv | AT christophlossin compromisedfunctioninthenav12dravetsyndromemutationr1312t AT xiuyushi compromisedfunctioninthenav12dravetsyndromemutationr1312t AT michaelarogawski compromisedfunctioninthenav12dravetsyndromemutationr1312t AT shinichihirose compromisedfunctioninthenav12dravetsyndromemutationr1312t |