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Title: Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in Caenorhabditis elegans
Authors: Huang, Yung-Chi
Pirri, Jennifer K.
Rayes, Diego
Gao, Shangbang
Mulcahy, Ben
Grant, Jeff
Saheki, Yasunori
Francis, Michael M.
Zhen, Mei
Alkema, Mark J.
Keywords: Science::Medicine
Issue Date: 2019
Source: Huang, Y.-C., Pirri, J. K., Rayes, D., Gao, S., Mulcahy, B., Grant, J., . . . Alkema, M. J. (2019). Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in Caenorhabditis elegans. eLife, 8, e45905-. doi:10.7554/eLife.45905
Journal: eLife
Abstract: Mutations in pre-synaptic voltage-gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic and decreased GABAergic transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin-dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.
ISSN: 2050-084X
DOI: 10.7554/eLife.45905
Rights: © 2019 Huang et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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