Cytoplasmic tail diversity determines the effector bias of the adhesion GPCR ADGRL2.

The class B2 adhesion G protein-coupled receptors (aGPCRs) combines cell adhesion with GPCR signaling to control diverse biological processes. How aGPCRs interact with distinct groups of effectors including G proteins, arrestins, and G protein-coupled receptor kinases (GRKs) remains unclear. Here, we find that diversity in the aGPCR intracellular tail modulates G protein activation, arrestin-3 recruitment, and GRK selectivity in aGPCR ADGRL2. The C-terminal tail of ADGRL2 is required for G protein activation and arrestin-3 recruitment. ADGRL2 with an intact tail recruits arrestin-3 in the absence of G protein activation, suggesting arrestin-3-biased signaling. Alternative splicing of the ADGRL2 tail modulates G protein activation and arrestin-3 binding independently. GRKs are important but not essential for arrestin-3 recruitment to ADGRL2. Moreover, GRK2 increases arrestin-3 recruitment only in a subset of ADGRL2 variants. Collectively, these results show that the interactions of class B2 aGPCRs and arrestin are distinct from class A GPCRs and that ADGRL2 splicing determines effector bias.