Phylogeny of the cholecystokinin/gastrin family

The neuroendocrine peptides cholecystokinin (CCK) and gastrin, originally identified in mammals, are characterized by a common amidated C-terminal tetrapeptide sequence, Trp-Met-Asp-Phe.NH2, which also constitutes the minimal structure necessary for biological activity of both. Hence, it has been proposed that CCK and gastrin have evolved from a common ancestor. Although the occurrence of CCK/gastrin-related peptides has been suggested in representatives of several invertebrate phyla, the evidence, mostly based on immunoreactivity, has not been substantiated by peptide identification. Instead, CCK/gastrin-specific antibodies might be cross-reacting with Asp-Phe-amides, like the lymnaDFamides, isolated from the freshwater snail Lymnaea stagnalis. Cionin, isolated from Ciona intestinalis, a representative of the protochordates that occupy a key position at the transition to vertebrates, so far represents the oldest genuine member of the CCK/gastrin family, dating the emergence of these peptides back to at least 500 million years ago. The CCK/gastrin family appears to be represented in the whole chordate phylum, and in addition to mammals, CCK and gastrin have recently been identified in a number of nonmammalian species representing the major vertebrate classes, including fishes, amphibians, reptiles, and birds. This now makes it possible to consider the CCK/gastrin phylogeny based on structural information. A duplication of the ancestral gene appears to have already occurred before or during the appearance of cartilaginous fish, giving rise to two peptides most likely homologous to mammalian CCK and gastrin. Indicative of a function of gastrin, the acid secretory system appears to have developed concomitantly in sharks. The segregation of CCK and gastrin early in vertebrate evolution resembles the situation in other peptide families, in accordance with a suggested widespread pattern of multiplication within vertebrate peptide and protein families around 400 million years ago. At the amphibian level, two separate peptide systems, resembling mammalian CCK and gastrin, have been characterized by identification of the mature bioactive peptides, cDNAs, gene structures, primary and secondary sites of gene expression, and their physiological actions. The overall gene structure, including exon/intron organization, is similar in all mammalian and nonmammalian CCK/gastrin genes. CCK is well conserved in all vertebrate species investigated, while the mammalian gastrins at first sight appear as a distinct group with little similarity to the nonmammalian gastrins outside the invariant C-terminal tetrapeptide and the C-terminal flanking peptide of the prohormone. However, evidence indicates that the transition from nonmammalian to mammalian gastrin may not be as dramatic as first anticipated. In conclusion, the CCK/gastrin family appears to be represented in most, if not all, chordates, to which group it may also be limited. The two major classes, CCK and gastrin, probably arose as distinct peptide systems early in vertebrate history. While CCK is well conserved in all vertebrates, a major structural change of gastrin accompanied the transition to mammals.