LRRC57/RABIN is a presynaptic inhibitor of Rab GTPases in glutamatergic neurons
Synaptic vesicle cycling, if not properly constrained, can result in excessive neurotransmitter release and subsequent neural pathology. Rab GTPases orchestrate synaptic vesicle trafficking through GTP-dependent interactions with effector proteins, but the restraining mechanism of these interactions is unknown. Here we identify LRRC57 (or RABIN for RAB INhibitor), a conserved brain-enriched…
The LRRC57/RABIN protein, a conserved brain-enriched molecule found in glutamatergic synapses, acts as an inhibitor of Rab GTPases. Rab GTPases are crucial in regulating synaptic vesicle trafficking via GTP-dependent interactions with effector proteins, but the restraint mechanism of these interactions remains unclear. The study identifies LRRC57/RABIN as a protein that binds multiple GTP-loaded synaptic Rabs and competes with them for access to their effectors.
When Rabin is lost, glutamate release increases, vesicle pools expand, vesicle turnover accelerates, and circuit hyperexcitability occurs, leading to epileptiform activity. This hyperexcitability can be mitigated by an antiepileptic agent that targets presynaptic function. However, overexpression of the Rabin gene suppresses neurotransmitter release and protects against induced seizures, as well as persistent epileptiform discharges.
In summary, LRRC57/RABIN establishes a noncanonical decoy-effector mechanism that constrains presynaptic Rab signaling, preserving excitatory circuit stability.
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