The Mechanobiology of the GluD1 Receptor at the Synaptic Cleft

The post-synaptic glutamate delta 1 receptor (GluD1), despite being considered an ionotropic receptor, has not been shown to function in a classically ionotropic way. Instead, it bridges the pre- and post-synaptic cleft through its interaction with the intermediary protein Cerebellin 2 (Cbln2) and the pre-synaptic protein Neurexin 1 beta with the splice site four insert (Nrx1β+). Through biophysical approaches that assess protein-protein interactions under physical forces, we demonstrate that: 1) the splice site 4 insert is necessary for cooperativity in the tripartite bond binding propensity and sustainability, 2) force at ~10 piconewton level prolongs single GluD1–Cbln2–Nrx1β+ bonds, 3) cells generate endogenous force through GluD1, 4) GABA but not D-serine enhances bond lifetime under force and both GABA and D-serine increase neuron-generated force on GluD1, and 5) GluD1-mediated intraneuronal calcium signaling patterns are altered when cells are prevented from exerting greater than 12 pN forces vs when cells are permitted to exert up to 56 pN forces, which correlate with differentiation markers, demonstrating force is important for synaptogenesis. These findings reveal mechanistic insights into GluD1 function and suggest new directions for understanding its role in synaptogenesis and disease states.

Date

2025-04-30

Resource Type

Text

Resource Subtype

Dissertation

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