Neurons are unique in having dendrites that extend far away from their cell bodies. Mitochondria located in the dendrites can be separated from the nucleus for long distances. The mechanism of bigenomic coordination is of particular importance to cytochrome oxidase (CO), which has subunits that are encoded in both the nuclear and mitochondrial DNA. GA-binding protein (GABP) is a transcription factor that is required for the promoter activity of mitochondrial transcription factor A as well as several nuclear-encoded CO subunits. Thus, GABP may play a key role in coordinating the transcription of both mitochondrial and nuclear-encoded subunits of CO. The goal of the present study was to determine if GABP was expressed in neurons and whether and how it responded to increased neuronal activity. Using primary neuronal cultures, the beta-subunit of GABP was localized immunocytochemically to both the cytoplasm and the nucleus, whereas the alpha-subunit was expressed mainly in the nucleus. In KCl-treated cultures, immunoreactivity for both alpha- and beta-subunits was significantly increased in the nucleus compared with untreated sister cultures. The induction of GABP preceded that of CO gene expression from the two genomes, which, in turn, preceded that of CO activity. Thus, our data suggest that neuronal activity regulates subunit concentrations of GABP in the nucleus, and GABP may be a critical sensor of changes in neuronal activity. Our data are also consistent with the postulated role of GABP as a coordinator of both mitochondrial and nuclear transcription for subunits of CO in neurons.