The N terminus-only function of adhesion GPCRs
Adhesion G protein-coupled receptors (GPCRs) mediate dual functions: one classical via G-protein pathways and a second solely by their extracellular N termini (N terminus-only/trans/seven transmembrane domain-independent).
The N terminus-only function can occur separately or together with G protein mediated signaling. The N terminus has large flexibility. In some cases it is released from the receptor whereas in others it remains attached to the rest of the receptor, resulting in different physiological outcomes.
Differential splicing also produces variants containing only the aGPCR N terminus and provides several alternatives for how the N terminus-only function is realized.
The N terminus can serve either as a ligand for receptors on neighboring cells or as a modulator of other signaling cascades, thereby mediating signals by itself.
The N terminus-only function is implicated in several diseases, and targeting the N terminus has substantial pharmacological potential.
https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(25)00004-5
