Clustering of the Adhesion-GPCR Latrophilin-3 Drives Excitatory Synapse Assembly
- 1Stanford University
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.
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BibTeX
@misc{huyan2026clustering,
title = {{Clustering of the Adhesion-GPCR Latrophilin-3 Drives Excitatory Synapse Assembly}},
author = {C. Huyan and A. Bhat and G. Landa and T. C. Sudhof and A. R. Dunn},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.757884},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.757884v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Clustering of the Adhesion-GPCR Latrophilin-3 Drives Excitatory Synapse Assembly
AU - C. Huyan
AU - A. Bhat
AU - G. Landa
AU - T. C. Sudhof
AU - A. R. Dunn
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.757884
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.757884v1
AB - 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.
ER -