RT Journal Article SR Electronic T1 Dopamine Negatively Regulates the NCA Ion Channels in C. elegans JF bioRxiv FD Cold Spring Harbor Laboratory SP 097394 DO 10.1101/097394 A1 Irini Topalidou A1 Kirsten Cooper A1 Michael Ailion YR 2016 UL http://biorxiv.org/content/early/2016/12/30/097394.abstract AB 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, but its precise cellular role and regulation are unclear. We previously found that NCA-1, one of two Caenorhabditis elegans orthologs of NALCN, is activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Using a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player in the Gq-Rho-NCA pathway. We find that GRK-2 acts in the head acetylcholine neurons to positively regulate locomotion and Gq signaling. Using structure-function analysis, we show that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Our genetic epistasis data suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively regulate NCA-1 and NCA-2 activity. We also demonstrate that dopamine, through DOP-3, negatively regulates NCA-1 and NCA-2 function. Thus, dopamine regulates activity of the NCA channels through G protein signaling pathways.Author summary Dopamine is a neurotransmitter that acts in the brain by binding seven transmembrane receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins). Neuronal G proteins often function by modulating ion channels that control membrane excitability. Here we identify a molecular cascade downstream of dopamine in the nematode C. elegans that involves activation of the dopamine receptor DOP-3, activation of the G protein GOA-1, and inactivation of the NCA-1 and NCA-2 ion channels. We also identify a kinase (GRK-2) that phosphorylates and inactivates the dopamine receptor DOP-3, thus leading to inactivation of GOA-1 and activation of the NCA channels. Thus, this study connects dopamine signaling to activity of the NCA channels through G protein signaling pathways.