The G protein-coupled receptor GPR10 is highly localized to areas of the brain. In an effort to reveal transcriptional determinants of this tissue specificity, we recognized a putative NRSE (neuron-restrictive silencer element) located in the 5' promoter region of the gene. The cognate NRSE binding protein NRSF (neuron-restrictive silencer factor) restricts gene expression to mature neurons and endocrine cells by repressing their transcription in non-neuronal/-endocrine cells. In cell lines where NRSF-mediated gene repression has been functionally established, the activity of the GPR10 promoter was repressed in a manner consistent with NRSE-dependent regulation. A specific point mutation to confer non-functionality of the NRSE revealed a 10-fold de-repression of reporter gene expression. In contrast, in the GPR10-expressing cell line GH3, mRNA transcripts of NRSF were undetectable and suppression of promoter activity was not observed. However, transfection of a rat NRSF expression vector resulted in significant repression of transcription, which was reversed by mutation of the NRSE. In conclusion, we demonstrate that the GPR10 gene is specifically regulated by NRSF, and suggest this to be a contributory factor in the tissue-specific distribution of GPR10 in vivo.