The sodium-calcium exchanger (NCE) plays a critical role in diverse processes in many different tissues including heart, nerve, and kidney. Surprisingly, the NCE is encoded by a single gene. We have isolated and sequenced a rat renal NCE clone, denoted F1, that was identical to previous rat NCEs, except for two unique sequences: one in the 5'-untranslated region and the other at a site of alternative splicing in the coding sequence. To explore these regions further, we examined NCE transcripts in several tissues using "rapid amplification of cDNA 5'-ends" and polymerase chain reaction amplification. Three species were identified each with a different 5'-end exon spliced to a common NCE core at nucleotide -34 in the 5'-untranslated region. Based on Northern analysis, each of these species had a unique tissue distribution. Whereas the F1 5'-end variant was abundantly expressed only in kidney, a second variant was expressed mostly in heart, and the third variant was expressed ubiquitously elsewhere. Investigation of the region of alternative splicing in the coding sequence also revealed tissue-specific expression of five major species. These findings indicate that the NCE expression is controlled and regulated under the influence of different promoters in a tissue-specific fashion. Therefore, we propose that the structural complexity of the single NCE gene allows it to respond independently to the unique demands of different environments.