G protein-coupled receptors (GPCRs) are the most pharmaceutically exploited family of proteins, being the target for 34% of drugs. Although GPCRs also exist in as oligomeric forms, the only GPCR oligomers to be targeted by FDA-approved drugs act through GPCRs in complex with a receptor activity-modifying protein (RAMP), a family of three single transmembrane proteins.

G protein-coupled receptors (GPCRs) are the most pharmaceutically exploited family of proteins, being the target for 34% of drugs. Although GPCRs also exist in as oligomeric forms, the only GPCR oligomers to be targeted by FDA-approved drugs act through GPCRs in complex with a receptor activity-modifying protein (RAMP), a family of three single transmembrane proteins. RAMPs are ubiquitously expressed and have been shown to interact with several different GPCRs across multiple GPCR families. Despite the substantial implications in drug development, only a handful of GPCRs have been tested for interactions with RAMPs.

A recent publication in Science Advances presented the work of an international collaboration with researchers from Rockefeller University, where it was determined that GPCR-RAMP interactions are indeed more widespread than previously reported. To obtain these new insights that describe the complete interactome of secretin-like GPCRs with RAMPs, the team developed a new multiplexed immunoassay. Using a dedicated antibody validation scheme, the study showed that the GPCR-specific antibodies could capture the majority of GPCR-RAMP complexes with the applied protocol. Ten additional secretin-like GPCRs, chemokine receptors, and orphan receptors were also found to interact with RAMPs. Importantly, the strategy will now be useful to expand the search for additional GPCR complexes within cellular membranes of other cell lines and tissues.

By Emily Lorenzen and Jochen Schwenk