Novel fish-derived adrenomedullin in mammals: structure and possible function

Adrenomedullin (AM) has been recognized as a member of the calcitonin (CT)/CT gene-related peptide (CGRP) family. However, an independent AM family consisting of five paralogous peptides exists in teleost fish. Among them, the peptide named AM1 is an ortholog of mammalian AM as determined by the linkage analysis of orthologous genes and the presence of proAM N-terminal 20 peptide (PAMP)-like sequence in the prosegment. Since the peptides named AM2 and 3 are distinct from other members with respect to the precursor sequence, tissue distribution of the transcripts, and exon-intron organization, we searched for their mammalian orthologs from genome databases, which resulted in an identification of AM2 in human, rat, and mouse. AM2 was expressed abundantly in the submaxillary gland, kidney, and some vascular and digestive tissues of mice. AM2 injected in vivo induced potent cardiovascular and renal effects in mice. In the heart and kidney of mice, AM2 was localized in endothelial cells of the coronary vessels and in glomeruli and vasa recta, respectively. AM2 increased cAMP accumulation in cells expressing human CT receptor-like receptor (CRLR) and one of receptor activity-modifying proteins (RAMPs), but it was no more potent than CGRP and AM. AM2 was also less potent than CT in cells expressing CT receptor and RAMP. There remains a possibility that a new AM2-specific receptor or an additional RAMP that enables CRLR to be an AM2-specific receptor, exists in mammals.