Adhesion G-protein coupled receptor (aGPCR) (aGPCR)

Adhesion G-protein coupled receptors (aGPCRs) are a distinct family of 33 human receptors characterized by large N-terminal extracellular domains (ECDs) and a unique autoproteolytic activation mechanism [4, 9, 12]. They are defined by the presence of a GPCR-Autoproteolysis Inducing (GAIN) domain, which cleaves the receptor into an extracellular fragment (NTF) and a membrane-spanning fragment (CTF) that remain non-covalently associated [2, 8, 9]. aGPCRs function as both adhesion molecules and signaling platforms, often acting as mechanosensors that translate physical forces into intracellular signals via an internal Stachel (tethered agonist) sequence [1, 5, 8]. These receptors play essential roles in organ development, immune regulation, and synaptic function, and their dysregulation is implicated in cancer metastasis, neurological disorders such as Usher syndrome, and inflammatory conditions [4, 8, 12, 16]. Although no drugs targeting aGPCRs are currently FDA-approved, they represent a significant frontier for drug discovery, with ongoing research into small molecules, synthetic peptides, and antibodies designed to modulate their complex structural transitions and signaling pathways [4, 6, 11, 13].

Other names

Adhesion GPCRClass B2 GPCRGRAFS Adhesion familyaGPCR

Activation primarily occurs through tethered agonism, where a conserved Stachel sequence is exposed to the seven-transmembrane domain following autoproteolysis or mechanical force. Other mechanisms include ligand-induced conformational changes and mechanical force-induced signaling.