SUMMARY Adhesion G protein-coupled receptors (aGPCR) function as metabotropic mechanosensors in the nervous system and other organs. aGPCR are heavily spliced forecasting an extraordinary molecular structural diversity. Many predicted isoforms lack the transmembrane (7TM) signaling subunit, but to what extent these non-GPCR isoforms are produced and what physiological purpose they serve is unknown. Alternative splicing through intron retention of ADGRL/Latrophilin/Cirl mRNA in Drosophila generates transcripts encoding unconventional proteins with an extracellular domain anchored by a single transmembrane helix (Cirl 1TM ). Here, we show that Cirl 1TM transcripts are translated in vivo and that Cirl 1TM binds Cirl 7TM N-terminal fragment-dependently. This interaction enables mechanosensory neurons to distinguish input intensities through Gα o -dependent signaling. Similarly, a direct interaction was found for mammalian GPR126/ADGRG6 isoforms. Together, our findings define intron retention and isoform-specific heteromerization as extraordinary molecular strategies to adjust Cirl -dependent mechanosensation and demonstrate physiological relevance of versatile aGPCR isoform repertoire to tune cellular responsiveness.

Intron retention of an adhesion GPCR generates single transmembrane-helix isoforms to enable 7TM-adhesion GPCR function