Trans-synaptic interaction of orphan GPCR GPR88 and adhesion GPCR BAI3 through C1ql1 maintains synapse integrity.

Climbing fiber–localized GPR88 regulates climbing fiber–Purkinje cell synapses in the cerebellum and associative learning behaviors, identifying C1ql1 as its ligand.

• Why it matters: GPR88 is an orphan GPCR linked by genetics to neuropsychiatric conditions, but its endogenous ligand and downstream pathways were unresolved.
• What they did: The study tested whether CF-localized GPR88 responds to the CF-secreted protein C1ql1, showing C1ql1 activates biased Gq signaling to enhance CF synapses. It also demonstrated that GPR88 anchors C1ql1 and enables a tripartite complex with postsynaptic adhesion GPCR BAI3 in vitro.
• The result: These findings resolve GPR88’s orphan status and suggest a mechanism where a secreted protein links two GPCRs to fine-tune synaptic signaling at pre- and postsynaptic sites.