Reexamining the activation mechanisms of adhesion G protein–coupled receptors

Adhesion G protein-coupled receptors (aGPCRs) are a unique GPCR family defined by large, modular extracellular regions (ECRs) and a conserved seven-transmembrane (7TM) domain. These domains enable aGPCRs to mediate cell-cell and cell-matrix communication, integrate mechanical and chemical signals, and regulate diverse biological processes including neurodevelopment, angiogenesis, and immune response. Traditionally, models of aGPCR activation have focused on the canonical tethered agonist (TA) mechanism, in which autoproteolytic cleavage reveals an intrinsic peptide (TA) that activates the 7TM domain. However, mounting structural, functional, and biophysical evidence indicates that this TA-dependent mechanism is insufficient to explain all aGPCR functions, especially in cleavage-deficient receptors or under physiological forces. A distinct ECR-dependent mechanism has emerged in which allosteric regulation or structural changes in the ECR directly modulate receptor signaling independent of TA exposure. This ECR-dependent model offers reversible, tunable signaling that can accommodate both pulling and compressive forces, expanding traditional views of aGPCR activation. Here, we critically examine current evidence for TA- and ECR-dependent mechanisms, discuss their structural underpinnings, and propose a unified, biological context-dependent framework integrating all known activation modes. This Review advances understanding of aGPCR signaling and provides a basis for therapeutic approaches targeting aGPCRs.