Molecular biological studies of the cardiac sodium-calcium exchanger

The intron-exon organization of the entire human Na-Ca-exchanger gene NCX1 and of the central part of the related gene NCX2 has been determined. The NCX1 gene is at least 75 kb long and consists of at least 12 exons, the two largest (the 2nd and the 12th) coding for the N-terminal half of the exchanger sequence and for the last three C-terminal transmembrane domains. They also code for the 3.3-kb 3'-untranslated region and account for more than 90% of the length of the mature mRNA. The remainder of the NCX1 (NCX2) gene, coding for a putative cytoplasmic regulatory domain, is split into 9 (7) small exons. In spite of the limited (65%) average homology of the two cDNAs, analogous exons are readily identified within this portion of the two genes based on their high (80-95%) pairwise homology and similar patterns of differential splicing in brain. Human YAC clones have been identified in the CEPH library, which contain the entire NCX1/2 and NCKX1 (retinal rod exchanger) genes, and are used for chromosomal localization of the three genes. A distant homolog of the mammalian NCX genes has been identified in the C. elegans EST database and has been completely sequenced. It encodes a 20% shorter protein, which has an average 55% homology to human NCX1, and lacks most of the region that is known to be encoded by multiple differentially spliced exons in vertebrates. Comparison of available data on the gene structure of the NCX homologs in various species suggests that this protein has emerged in the primitive nervous system and has been subsequently adapted to other cellular environments by the use of novel domains, encoded in additional exons.