Receptor activity-modifying proteins; multifunctional G protein-coupled receptor accessory proteins

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Receptor activity-modifying proteins (RAMPs) are single-pass membrane proteins.
• RAMPs were initially identified for their role in modulating calcitonin receptor-like receptor (CLR) pharmacology.
• RAMPs are now known to interact with a broad spectrum of G protein-coupled receptors (GPCRs).

Purpose of the Study:

• To review recent structural and interaction data concerning RAMPs and GPCRs.
• To elucidate the mechanisms by which RAMPs influence GPCR function.
• To highlight the therapeutic potential of targeting GPCR-RAMP interactions.

Main Methods:

• Structural analysis of extracellular domains (ECDs) of CLR complexed with RAMP1 or RAMP2.
• Review of literature on RAMP interactions across different GPCR families (B, A, and C).
• Examination of RAMP-mediated effects on receptor expression, trafficking, ligand binding, and G protein coupling.

Main Results:

• Structural insights reveal how RAMPs direct ligand binding to CLR.
• RAMPs interact with a diverse range of GPCRs beyond family B.
• RAMPs significantly influence multiple aspects of GPCR cell surface behavior and signaling.

Conclusions:

• RAMP interactions with GPCRs are extensive and functionally significant.
• The structural basis of RAMP-GPCR modulation provides a foundation for drug discovery.
• Targeting GPCR-RAMP interfaces presents viable therapeutic strategies, as exemplified by migraine treatments.