Dawn of a New RAMPage

• Published in: Trends in pharmacological sciences (Regular ed.) Vol. 41; no. 4; pp. 249 - 265
• Main Authors: Serafin, D. Stephen, Harris, Natalie R., Nielsen, Natalie R., Mackie, Duncan I., Caron, Kathleen M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2020
• Subjects: adrenomedullin; Animals; Antibodies, Monoclonal, Humanized - pharmacology; Calcitonin Gene-Related Peptide - metabolism; Calcitonin Gene-Related Peptide Receptor Antagonists - pharmacology; CGRP; coevolution; erenumab; G-protein-coupled receptor; Humans; Molecular Targeted Therapy; Mutation; receptor activity-modifying proteins (RAMPs); Receptor Activity-Modifying Proteins - genetics; Receptor Activity-Modifying Proteins - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Signal Transduction - drug effects; receptor activity-modifying proteins (RAMPs); adrenomedullin; erenumab; CGRP; coevolution; G-protein-coupled receptor
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2020.01.009

Receptor activity-modifying proteins (RAMPs) interact with G-protein-coupled receptors (GPCRs) to modify their functions, imparting significant implications upon their physiological and therapeutic potentials. Resurging interest in identifying RAMP–GPCR interactions has recently been fueled by coevolution studies and orthogonal technological screening platforms. These new studies reveal previously unrecognized RAMP-interacting GPCRs, many of which expand beyond Class B GPCRs. The consequences of these interactions on GPCR function and physiology lays the foundation for new molecular therapeutic targets, as evidenced by the recent success of erenumab. Here, we highlight recent papers that uncovered novel RAMP–GPCR interactions, human RAMP–GPCR disease-causing mutations, and RAMP-related human pathologies, paving the way for a new era of RAMP-targeted drug development. RAMPs interact with GPCRs to regulate receptor function.RAMP–GPCR coevolution studies suggest that RAMPs globally interact with GPCRs.Over the past year, two studies expanded the RAMP–GPCR interactome using both multiplexed suspension bead array (SBA) and bioluminescence resonances energy transfer (BRET) methodologies.Human mutations in RAMP–GPCR pairings have been identified and linked to human disease, including a mutation in calcitonin receptor-like receptor (CLR), associated with hydrops fetalis, and mutations in RAMP2, associated with glaucoma.For the first time, the US FDA approved a GPCR-directed antibody against RAMP1–CLR, which reduces the number of migraine days patients experience.The expanded RAMP–GPCR interactome and pivotal success of the first targeted therapy of RAMP–GPCR pairs has ushered in a new RAMPage.