The effects of somatostatin hormones are mediated by a family of five different seven-helix transmembrane spanning receptors (SSTR1-5). The expression of the five different SSTR subtypes displays a complex temporal- and tissue-specific pattern. To investigate the molecular mechanisms controlling the different expression patterns of the SSTRs, we cloned the 5'-flanking region of the human SSTR2 gene. Characterization of the SSTR2 promoter resulted in the identification of a novel initiator element (SSTR2inr). Transcriptional activity of the SSTR2inr is dependent on the presence of a binding site (E-box) for basic helix-loop-helix (bHLH) transcription factors. By screening a mouse brain cDNA expression library we isolated a cDNA coding for the bHLH transcription factor SEF-2. SEF-2 binds to the E-box present in the SSTR2inr, both in vitro and in vivo and activates transcription from the SSTR2inr. A single point mutation within the E-box eliminates binding of SEF-2 and results in a complete loss of transcriptional activity of the SSTR2inr. Furthermore, DNA binding studies demonstrate that the basal transcription factor TFIIB can be tethered to the SSTR2inr through physical interaction with SEF-2. In summary, the SSTR2inr represents a novel type of initiator element that confers gene expression in the absence of a TATA-box or binding sites for other known initiator factors, like YY-1 or USF.