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

Area of Science:

• Endocrinology
• Comparative genomics
• Cardiovascular research

Background:

• Adrenomedullin (AM) is part of the calcitonin (CT)/CT gene-related peptide (CGRP) family.
• Teleost fish possess an independent AM family with five paralogous peptides.
• AM1 is an ortholog of mammalian AM, identified via gene linkage and pro--AM N-terminal 20 peptide (PAMP)-like sequences.

Purpose of the Study:

• To identify mammalian orthologs of fish AM2 and AM3 peptides.
• To investigate the physiological roles and receptor interactions of the identified mammalian AM2.

Main Methods:

• Genome database searches for mammalian orthologs of fish AM2 and AM3.
• Analysis of AM2 tissue distribution in mice using transcript analysis.
• In vivo administration of AM2 to assess cardiovascular and renal effects in mice.
• Localization studies of AM2 in mouse heart and kidney.
• In vitro cAMP accumulation assays in cells expressing various receptors and receptor activity-modifying proteins (RAMPs).

Main Results:

• AM2 was identified as a mammalian ortholog, expressed in mouse submaxillary gland, kidney, and vascular/digestive tissues.
• AM2 demonstrated potent cardiovascular and renal effects in vivo.
• AM2 localized to endothelial cells in the heart and specific renal structures.
• AM2 increased cAMP in cells with CT receptor-like receptor (CRLR) and RAMPs, but with lower potency than CGRP or AM.

Conclusions:

• AM2 represents a novel mammalian peptide with significant cardiovascular and renal functions.
• AM2 interacts with the CRLR/RAMP system, though its potency differs from related peptides.
• The existence of a potential AM2-specific receptor or additional RAMPs in mammals warrants further investigation.