New methods for researching accessory proteins.

Receptor activity-modifying proteins (RAMPs) control the pharmacology of the receptors for the calcitonin family of peptide hormones. There are five of these peptides: calcitonin, calcitonix/calcitixin gene-related peptide (CGRP), adrenomedullin, amylin, and now adrenomedullin 2. The calcitonin receptor is specific for calcitonin when expressed alone but it can function as an amylin or CGRP receptor when co-expressed with a RAMP. The calcitonin receptor-like receptor (CRLR) will not reach the cell surface without any one of the three RAMP proteins to function as either a CGRP or adrenomedullin receptor. This system was discovered more than 6 yr ago. At the time, it was reasonable to think that nature would employ accessory proteins, such as the RAMPs, to enable flexible signaling systems for other ligand families and that these would be discovered in time. In reality, many more new peptide ligands have been discovered than accessory proteins. Why is this? Developments in bioinformatics facilitate the discovery of both seven transmembrane ligands and accessory proteins. Proteomics and transcriptomics can be used together to define likely accessory proteins that can be experimentally tested. Comparative genomics was used in the discovery of adrenomedullin 2. The existence of multiple RAMPs within several species of fish suggests an alternative endocrinology. Finally, genetics offers a direct view of receptors, ligands, and accessory proteins in human disease--either as causative or contributing factors.