Homeostatic regulation of neural activity is an elegant system whose effect is finely tuned to maintain stability of synaptic or circuit function. This type of regulation counteracts external perturbations to maintain a set point of activity. The molecular mechanisms by which such regulation takes place are largely unknown. Included in this regulatory system are CaV2.1 calcium channels, which are encoded by the cacophony (cac) gene found in Drosophila melanogaster (Davis, 2012). We used the Gal4-UAS system to identify interactors of the cac gene by use of RNAi. We observed that high expression of gain-of-fuction (GOF) mutations in CaV2.1 that mimic migraine-causing mutations in people induces lethality in Drosophila. In a genetic screen, we evaluated flies carrying the neuronally expressed GOF calcium channel driven at a low level to sensitize the system as well as RNAi against candidate genes of interest. These animals were compared to controls which did not contain both constructs. Using this data, we are able to assess the impact of RNAi knockdown of candidate genes via enhancement or suppression of lethality in the GOF calcium channel background to identify interactors. Among the (pending) RNAi candidates screened, the data indicate an interaction with (pending) genes with cac. Currently, we are performing neuromuscular junction staining to investigate possible roles of one strong candidate, PLC21C (the Drosophila PLC-beta), in development by looking at synaptic development. The genetic data are consistent with a previously identified role for PLC21C in regulating homeostatic control of synaptic function."