EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling
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
Affiliations
Catrina M Loucks
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, Canada
Kwangjin Park
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, Canada
Denise S Walker
Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
Andrea H McEwan
Djavad Mowfaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada
Tiffany A Timbers
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, Canada
Evan L Ardiel
Djavad Mowfaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada
Laura J Grundy
Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
Chunmei Li
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, Canada
Jacque-Lynne Johnson
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, Canada
Julie Kennedy
School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
Oliver E Blacque
School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
William Schafer
Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
Catharine H Rankin
Djavad Mowfaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada; Department of Psychology, University of British Columbia, Vancouver, Canada
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, Canada
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.
