Dopamine negatively modulates the NCA ion channels in C. elegans

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 gqand 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 gosignaling 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. © 2017 topalidou et al.