Clustering of the Adhesion-GPCR Latrophilin-3 Drives Excitatory Synapse Assembly

Authors

Huyan, C., Bhat, A., Landa, G., Sudhof, T. C., Dunn, A. R.

Abstract

Precise control of synapse formation is essential for brain function. Adhesion-GPCRs combine adhesion, signaling, and scaffold recruitment to regulate synapse formation, yet their mechanisms of action remain unclear. Here, we identify nanoscale clustering of the adhesion-GPCR Latrophilin-3 as a key mechanism regulating excitatory synapse assembly. We find that endogenous Latrophilin-3 forms densely packed nanoclusters, with larger nanoclusters enriched at excitatory synapses. To probe the functional significance of Latrophilin-3 clustering, we engineered an optogenetically controlled Latrophilin-3. Light-induced Latrophilin-3 clustering triggered robust excitatory synapse formation, which required both Latrophilin-3-mediated G-protein signaling and postsynaptic scaffold recruitment. Strikingly, clustering of a mutant Latrophilin-3 lacking known ligand-binding domains still promoted synapse formation, indicating that Latrophilin-3 ligands induce synapse assembly primarily by clustering Latrophilin-3. Our findings suggest a general paradigm by which extracellular ligand-induced clustering activates adhesion-GPCRs by generating compartmentalized signaling, which in the case of Latrophilin-3, cooperates with postsynaptic scaffold recruitment to drive synapse assembly.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 15 Oct 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.