Heterodimers and family-B GPCRs: RAMPs, CGRP and adrenomedullin

• Published in: Biochemical Society transactions Vol. 32; no. Pt 5; p. 843
• Main Authors: Conner, A C, Simms, J, Hay, D L, Mahmoud, K, Howitt, S G, Wheatley, M, Poyner, D R
• Format: Journal Article
• Language: English
• Published: England 01-11-2004
• Subjects: Adrenomedullin; Amino Acid Sequence; Animals; Calcitonin Gene-Related Peptide - chemistry; Dimerization; Glycosylation; Humans; Intracellular Signaling Peptides and Proteins; Kinetics; Ligands; Membrane Proteins - chemistry; Molecular Sequence Data; Peptides - chemistry; Peptides - physiology; Protein Binding; Protein Structure, Tertiary; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins; Receptors, Calcitonin - chemistry; Receptors, Calcitonin Gene-Related Peptide - chemistry; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - physiology; Sequence Homology, Amino Acid
• ISSN: 0300-5127
• DOI: 10.1042/bst0320843

RAMPs (receptor activity-modifying proteins) are single-pass transmembrane proteins that associate with certain family-B GPCRs (G-protein-coupled receptors). Specifically for the CT (calcitonin) receptor-like receptor and the CT receptor, this results in profound changes in ligand binding and receptor pharmacology, allowing the generation of six distinct receptors with preferences for CGRP (CT gene-related peptide), adrenomedullin, amylin and CT. There are three RAMPs: RAMP1-RAMP3. The N-terminus appears to be the main determinant of receptor pharmacology, whereas the transmembrane domain contributes to association of the RAMP with the GPCR. The N-terminus of all members of the RAMP family probably contains two disulphide bonds; a potential third disulphide is found in RAMP1 and RAMP3. The N-terminus appears to be in close proximity to the ligand and plays a key role in its binding, either directly or indirectly. BIBN4096BS, a CGRP antagonist, targets RAMP1 and this gives the compound very high selectivity for the human CGRP(1) receptor.