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 protein in glutamatergic synapses that binds multiple GTP-loaded synaptic Rabs and competitively blocks access to their effectors. Loss of Rabin increased glutamate release, expanded vesicle pools, accelerated vesicle turnover, and produced circuit hyperexcitability with epileptiform activity, which was mitigated by an antiepileptic agent that targets presynaptic function. Conversely, overexpression of the Rabin gene suppressed neurotransmitter release and protected against induced seizures and persistent epileptiform discharges. Together, these findings define a noncanonical decoy–effector mechanism that constrains presynaptic Rab signaling to preserve excitatory circuit stability.
How LRRK2-dependent trafficking mechanisms regulate key components of synaptic transmission, including glutamatergic and GABAergic receptors, as well as astrocytic transporters are examined, highlighting how disruption of these processes affects neurotransmitter clearance, receptor activation, and ultimately E/I balanc...
Angela Di Iacovo, C. D'Agostino, Giulia Casoli et al.· Cellular and molecular neuro...· 0 citations
By linking these trafficking mechanisms to synaptic structure and ion channel function, this review situates GABAAR biogenesis within the broader framework of synaptic organization relevant to epilepsy and other neurological disorders.
Tahere Mohammadpour, R. Mohammadzadeh· Synapse· 0 citations
Synaptic plasticity is crucial for learning and memory. The presynaptic calcium sensor synaptotagmin 7 (syt7) regulates aspects of short-term plasticity (STP), but the underlying mechanisms remain unclear. Here, we show that alternative splicing of the syt7 juxtamembrane linker acts as a molecular switch at both bioche...
Nikunj Mehta, D. Larson, Mitch Wozney et al.· Proceedings of the National...· 0 citations
It is demonstrated that both pathway activation and amplification are required for a rapid and effective homeostatic response by integrating these two functions within a single molecular assembly, Neto-α ensures fast and efficient compensatory responses to perturbations.
Rosario Vicidomini, Tae Hee Han, Wen-Chieh Hsieh et al.· Proceedings of the National...· 0 citations
Structural, biochemical, and cellular evidence is integrated to advance a unifying hypothesis that PD-associated LRRK2 dysfunction arises from maladaptive stabilization of specific conformational and spatial states within a membrane-responsive signalling network, leading to persistent misregulation of Rab-dependent tra...
Oscar Arias-Carrión, Magdalena Guerra-Crespo, Daniel Ortuño-Sahagún et al.· International Journal of Mol...· 0 citations
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