A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels
Resurgent currents (INaR) produced by voltage-gated sodium channels are required for many neurons to maintain high-frequency firing and contribute to neuronal hyperexcitability and disease pathophysiology. Here, we show, for the first time, that INaR can be reconstituted in a heterologous system by...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-04-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/77558 |
| _version_ | 1828169754109542400 |
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| author | Yucheng Xiao Jonathan W Theile Agnes Zybura Yanling Pan Zhixin Lin Theodore R Cummins |
| author_facet | Yucheng Xiao Jonathan W Theile Agnes Zybura Yanling Pan Zhixin Lin Theodore R Cummins |
| author_sort | Yucheng Xiao |
| collection | DOAJ |
| description | Resurgent currents (INaR) produced by voltage-gated sodium channels are required for many neurons to maintain high-frequency firing and contribute to neuronal hyperexcitability and disease pathophysiology. Here, we show, for the first time, that INaR can be reconstituted in a heterologous system by coexpression of sodium channel α-subunits and A-type fibroblast growth factor homologous factors (FHFs). Specifically, A-type FHFs induces INaR from Nav1.8, Nav1.9 tetrodotoxin (TTX)-resistant neuronal channels, and, to a lesser extent, neuronal Nav1.7 and cardiac Nav1.5 channels. Moreover, we identified the N-terminus of FHF as the critical molecule responsible for A-type FHFs-mediated INaR. Among the FHFs, FHF4A is the most important isoform for mediating Nav1.8 and Nav1.9 INaR. In nociceptive sensory neurons, FHF4A knockdown significantly reduces INaR amplitude and the percentage of neurons that generate INaR, substantially suppressing excitability. Thus, our work reveals a novel molecular mechanism underlying TTX-resistant INaR generation and provides important potential targets for pain treatment. |
| first_indexed | 2024-04-12T02:57:22Z |
| format | Article |
| id | doaj.art-9523fdcf8a444e838dc5323b8a3e17e1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:57:22Z |
| publishDate | 2022-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-9523fdcf8a444e838dc5323b8a3e17e12022-12-22T03:50:46ZengeLife Sciences Publications LtdeLife2050-084X2022-04-011110.7554/eLife.77558A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channelsYucheng Xiao0https://orcid.org/0000-0002-0298-7158Jonathan W Theile1Agnes Zybura2Yanling Pan3Zhixin Lin4Theodore R Cummins5https://orcid.org/0000-0001-9509-6380Biology department, School of Science, Indiana University Purdue University Indianapolis, Indianapolis, United StatesIcagen LLC, 4222 Emperor Blvd #350, Durham, United StatesProgram in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United StatesBiology department, School of Science, Indiana University Purdue University Indianapolis, Indianapolis, United StatesIcagen LLC, 4222 Emperor Blvd #350, Durham, United StatesBiology department, School of Science, Indiana University Purdue University Indianapolis, Indianapolis, United StatesResurgent currents (INaR) produced by voltage-gated sodium channels are required for many neurons to maintain high-frequency firing and contribute to neuronal hyperexcitability and disease pathophysiology. Here, we show, for the first time, that INaR can be reconstituted in a heterologous system by coexpression of sodium channel α-subunits and A-type fibroblast growth factor homologous factors (FHFs). Specifically, A-type FHFs induces INaR from Nav1.8, Nav1.9 tetrodotoxin (TTX)-resistant neuronal channels, and, to a lesser extent, neuronal Nav1.7 and cardiac Nav1.5 channels. Moreover, we identified the N-terminus of FHF as the critical molecule responsible for A-type FHFs-mediated INaR. Among the FHFs, FHF4A is the most important isoform for mediating Nav1.8 and Nav1.9 INaR. In nociceptive sensory neurons, FHF4A knockdown significantly reduces INaR amplitude and the percentage of neurons that generate INaR, substantially suppressing excitability. Thus, our work reveals a novel molecular mechanism underlying TTX-resistant INaR generation and provides important potential targets for pain treatment.https://elifesciences.org/articles/77558sodium channelresurgent currentsFHFNavβ4dorsal root ganglion |
| spellingShingle | Yucheng Xiao Jonathan W Theile Agnes Zybura Yanling Pan Zhixin Lin Theodore R Cummins A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels eLife sodium channel resurgent currents FHF Navβ4 dorsal root ganglion |
| title | A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels |
| title_full | A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels |
| title_fullStr | A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels |
| title_full_unstemmed | A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels |
| title_short | A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels |
| title_sort | a type fhfs mediate resurgent currents through ttx resistant voltage gated sodium channels |
| topic | sodium channel resurgent currents FHF Navβ4 dorsal root ganglion |
| url | https://elifesciences.org/articles/77558 |
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