Novel Mutations in Synaptic Transmission Genes Suppress Neuronal Hyperexcitation in Caenorhabditis elegans
| Autor: | Seika Takayanagi-Kiya, Katherine A McCulloch, Yingchuan Qi, Salvatore J. Cherra, Yishi Jin |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Neurodegenerative QH426-470 medicine.disease_cause Synaptic Transmission 0302 clinical medicine immune system diseases Receptors Premovement neuronal activity 2.1 Biological and endogenous factors Receptors Cholinergic Aetiology skin and connective tissue diseases Genetics (clinical) Caenorhabditis elegans Cholinergic Genetics Mutation biology Cholinergic Neurons Cell biology locomotion sphingosine kinase Neurological Signal transduction Acetylcholine medicine.drug musculoskeletal diseases 1.1 Normal biological development and functioning seizure unc-17 Neurotransmission Investigations 03 medical and health sciences Underpinning research major facilitator superfamily domain (MFSD) proteins lipid acetylcholine transporter medicine Animals Caenorhabditis elegans Proteins Molecular Biology sphingosine kinase/sphk-1 Acetylcholine receptor sphk-1 Epilepsy acetylcholine receptor Neurosciences biology.organism_classification Brain Disorders 030104 developmental biology epilepsy 030217 neurology & neurosurgery |
| Zdroj: | G3: Genes, Genomes, Genetics, Vol 7, Iss 7, Pp 2055-2063 (2017) G3: Genes|Genomes|Genetics G3 (Bethesda, Md.), vol 7, iss 7 |
| ISSN: | 2160-1836 |
| Popis: | Acetylcholine (ACh) receptors (AChR) regulate neural circuit activity in multiple contexts. In humans, mutations in ionotropic acetylcholine receptor (iAChR) genes can cause neurological disorders, including myasthenia gravis and epilepsy. In Caenorhabditis elegans, iAChRs play multiple roles in the locomotor circuit. The cholinergic motor neurons express an ACR-2-containing pentameric AChR (ACR-2R) comprised of ACR-2, ACR-3, ACR-12, UNC-38, and UNC-63 subunits. A gain-of-function mutation in the non-α subunit gene acr-2 [acr-2(gf)] causes defective locomotion as well as spontaneous convulsions. Previous studies of genetic suppressors of acr-2(gf) have provided insights into ACR-2R composition and assembly. Here, to further understand how the ACR-2R regulates neuronal activity, we expanded the suppressor screen for acr-2(gf)-induced convulsions. The majority of these suppressor mutations affect genes that play critical roles in synaptic transmission, including two novel mutations in the vesicular ACh transporter unc-17. In addition, we identified a role for a conserved major facilitator superfamily domain (MFSD) protein, mfsd-6, in regulating neural circuit activity. We further defined a role for the sphingosine (SPH) kinase (Sphk) sphk-1 in cholinergic neuron activity, independent of previously known signaling pathways. Overall, the genes identified in our study suggest that optimal modulation of synaptic activity is balanced by the differential activities of multiple pathways, and the novel alleles provide valuable reagents to further dissect neuronal mechanisms regulating the locomotor circuit. |
| Databáze: | OpenAIRE |
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