Evolution of gastrointestinal hormones: the cholecystokinin/gastrin family

To describe recent advances in our understanding of the evolution of gastrointestinal hormones, with the gastrin/cholecystokinin (CCK) family as a model.

The release of 11 genomic sequences in the last year has provided a wealth of additional information on peptide hormone sequences. The alternative approach of reverse genetics has identified a separate class of CCK receptor ligands in the nematode Caenorhabditis elegans.

Three classes of ligands, insect sulfakinins, nematode neuropeptide-like proteins and vertebrate gastrins/cholecystokinins, have now been described for the family of CCK receptors. Although all terminate in an amidated phenylalanine, similarity between the three classes is minimal elsewhere in the sequences. The occurrence of separate gastrin and CCK genes in the dogfish Squalus acanthias dates the divergence of gastrin and CCK to at least 528 +/- 56 Myr ago. The presence of a polyglutamate sequence in marsupial gastrins suggests that the ability to bind ferric ions, which is a critical determinant of biological activity for nonamidated gastrins, was acquired at least 173 +/- 12 Myr ago. Comparison of gastrin or CCK sequences between species suggests that, apart from the C-terminal tetrapeptide amide that is required for receptor binding, conservation is largely restricted to the dibasic processing sites and to the C-terminal flanking peptides of gastrin and CCK. The independent conservation of the latter peptide may be either a consequence of a requirement for precise processing, or may indicate a separate function.