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Topalidou, I, Cooper, K, Pereira, L and Ailion, M (2017) Dopamine negatively modulates the NCA ion channels in C. elegans. PLoS Genet. 13:e1007032
The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels.
Acetylcholine/metabolism; Animals; Caenorhabditis elegans/drug effects; Caenorhabditis elegans/genetics; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism; Dopamine/pharmacology; Epistasis, Genetic; G-Protein-Coupled Receptor Kinases/genetics; G-Protein-Coupled Receptor Kinases/metabolism; GTP-Binding Protein alpha Subunits, Gi-Go/genetics; GTP-Binding Protein alpha Subunits, Gi-Go/metabolism; Gene Expression Regulation; Genome-Wide Association Study; Interneurons/drug effects; Interneurons/metabolism; Ion Channels/genetics; Ion Channels/metabolism; Mixed Function Oxygenases/genetics; Mixed Function Oxygenases/metabolism; Promoter Regions, Genetic; Receptors, Dopamine D2/genetics; Receptors, Dopamine D2/metabolism; Signal Transduction