Interaction of calcitonin-gene-related peptide with its receptors

The receptor for calcitonin-gene-related peptide (CGRP) is a heterodimer formed by calcitonin-receptor-like receptor (CRLR), a type II (family B) G-protein-coupled receptor, and receptor-activity-modifying protein 1 (RAMP1), a single-membrane-pass protein. It is likely that the first seven or so amino acids of CGRP (which form a disulphide-bonded loop) interact with the transmembrane domain of CRLR to cause receptor activation. The rest of the CGRP molecule falls into three domains. Residues 28–37 and 8–18 are normally required for high-affinity binding, while residues 19–27 form a hinge region. The 28–37 region is almost certainly in direct contact with the receptor; 8–18 may make additional receptor contacts or may stabilize an appropriate conformation of 28–37. It is likely that these regions of CGRP interact both with CRLR and with the extracellular domain of RAMP1.