EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling
Neurons throughout the mammalian brain possess non-motile cilia, organelles with varied functions in sensory physiology and cellular signaling. Yet, the roles of cilia in these neurons are poorly understood. To shed light into their functions, we studied EFHC1, an evolutionarily conserved protein re...
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doaj-187f16f490b2476e89b17a0470140d3f2021-05-05T17:26:36ZengeLife Sciences Publications LtdeLife2050-084X2019-02-01810.7554/eLife.37271EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signalingCatrina M Loucks0Kwangjin Park1Denise S Walker2Andrea H McEwan3Tiffany A Timbers4Evan L Ardiel5Laura J Grundy6Chunmei Li7Jacque-Lynne Johnson8Julie Kennedy9Oliver E Blacque10William Schafer11Catharine H Rankin12Michel R Leroux13https://orcid.org/0000-0003-0788-9298Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, CanadaDepartment of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, CanadaNeurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United KingdomDjavad Mowfaghian Centre for Brain Health, University of British Columbia, Vancouver, CanadaDepartment of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, CanadaDjavad Mowfaghian Centre for Brain Health, University of British Columbia, Vancouver, CanadaNeurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United KingdomDepartment of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, CanadaDepartment of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, CanadaSchool of Biomolecular and Biomedical Science, University College Dublin, Dublin, IrelandSchool of Biomolecular and Biomedical Science, University College Dublin, Dublin, IrelandNeurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United KingdomDjavad Mowfaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada; Department of Psychology, University of British Columbia, Vancouver, CanadaDepartment of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, CanadaNeurons throughout the mammalian brain possess non-motile cilia, organelles with varied functions in sensory physiology and cellular signaling. Yet, the roles of cilia in these neurons are poorly understood. To shed light into their functions, we studied EFHC1, an evolutionarily conserved protein required for motile cilia function and linked to a common form of inherited epilepsy in humans, juvenile myoclonic epilepsy (JME). We demonstrate that C. elegans EFHC-1 functions within specialized non-motile mechanosensory cilia, where it regulates neuronal activation and dopamine signaling. EFHC-1 also localizes at the synapse, where it further modulates dopamine signaling in cooperation with the orthologue of an R-type voltage-gated calcium channel. Our findings unveil a previously undescribed dual-regulation of neuronal excitability at sites of neuronal sensory input (cilium) and neuronal output (synapse). Such a distributed regulatory mechanism may be essential for establishing neuronal activation thresholds under physiological conditions, and when impaired, may represent a novel pathomechanism for epilepsy.https://elifesciences.org/articles/37271EFHC1juvenile myoclonic epilepsyciliasynapseCaenorhabditis elegans |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Catrina M Loucks Kwangjin Park Denise S Walker Andrea H McEwan Tiffany A Timbers Evan L Ardiel Laura J Grundy Chunmei Li Jacque-Lynne Johnson Julie Kennedy Oliver E Blacque William Schafer Catharine H Rankin Michel R Leroux |
spellingShingle |
Catrina M Loucks Kwangjin Park Denise S Walker Andrea H McEwan Tiffany A Timbers Evan L Ardiel Laura J Grundy Chunmei Li Jacque-Lynne Johnson Julie Kennedy Oliver E Blacque William Schafer Catharine H Rankin Michel R Leroux EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling eLife EFHC1 juvenile myoclonic epilepsy cilia synapse Caenorhabditis elegans |
author_facet |
Catrina M Loucks Kwangjin Park Denise S Walker Andrea H McEwan Tiffany A Timbers Evan L Ardiel Laura J Grundy Chunmei Li Jacque-Lynne Johnson Julie Kennedy Oliver E Blacque William Schafer Catharine H Rankin Michel R Leroux |
author_sort |
Catrina M Loucks |
title |
EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling |
title_short |
EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling |
title_full |
EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling |
title_fullStr |
EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling |
title_full_unstemmed |
EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling |
title_sort |
efhc1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2019-02-01 |
description |
Neurons throughout the mammalian brain possess non-motile cilia, organelles with varied functions in sensory physiology and cellular signaling. Yet, the roles of cilia in these neurons are poorly understood. To shed light into their functions, we studied EFHC1, an evolutionarily conserved protein required for motile cilia function and linked to a common form of inherited epilepsy in humans, juvenile myoclonic epilepsy (JME). We demonstrate that C. elegans EFHC-1 functions within specialized non-motile mechanosensory cilia, where it regulates neuronal activation and dopamine signaling. EFHC-1 also localizes at the synapse, where it further modulates dopamine signaling in cooperation with the orthologue of an R-type voltage-gated calcium channel. Our findings unveil a previously undescribed dual-regulation of neuronal excitability at sites of neuronal sensory input (cilium) and neuronal output (synapse). Such a distributed regulatory mechanism may be essential for establishing neuronal activation thresholds under physiological conditions, and when impaired, may represent a novel pathomechanism for epilepsy. |
topic |
EFHC1 juvenile myoclonic epilepsy cilia synapse Caenorhabditis elegans |
url |
https://elifesciences.org/articles/37271 |
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