Cara Khayat
BME PhD Defense Presentation

Date: 2025-04-15
Time: 10:30 am
Location / Meeting Link: Suddath Seminar Room 1128; https://emory.zoom.us/j/97710303583

Committee Members:
Cheng Zhu; Levi Wood, Andres Garcia, Ross Ethier, Machelle Pardue, Stephen Traynelis


Title: The Mechanobiology of the Glutamate Delta 1 Receptor

Abstract:
The glutamate delta 1 receptor (GluD1), despite sequence homology with related receptors, does not function in a classically ionotropic way. Instead, it bridges pre- and post-synaptic terminals by binding Neurexin 1β (Nrxn1β) via Cerebellin 2 (Cbln2), influencing synaptogenesis. Genetic links between GluD1 are associated with neurodevelopmental and neuropsychiatric disorders, such as schizophrenia, autism, and bipolar disorder. In this work, we hypothesize that GluD1–Cbln2–Nrxn1β binding in synaptogenesis is regulated by neuron-generated, cytoskeleton-driven forces at the synaptic cleft, and to support this GluD1 must be a mechanosensitive receptor which responds to force. To test this, we used advanced biophysical tools (Biomembrane Force Probe, DNA-based tension probes, and Tension Gauge Tethers) alongside traditional neurobiological techniques (immunohistochemistry, calcium dynamics) across three aims: 1) Generate protein/cell systems to study force-dependent 2D binding and cell-generated forces on the Nrxn1β–Cbln2–GluD1 complex. 2) Investigate the effects of neuromodulators like GABA and D-serine, and clinically relevant mutants, on GluD1’s mechanosensitivity. 3) Evaluate the role of these interactions in calcium signaling and synaptogenesis. In this work, we present the first affinity interactions of the tripartite GluD1–Cbln2–Nrxn1β, positive cooperativity that converts a slip bond to a catch bond in the tripartite binding, emphasizing the importance of force, and that cells generate endogenous pulling forces through the GluD1 receptor in the tripartite complex. Furthermore, we show that GluD1’s mechanosensitivity is impacted by neuromodulators GABA and D-serine, and a clinically relevant mutant changes GluD1’s binding properties and mechanosensitivity. Finally, we show that force in GluD1’s binding also translates into differences in signaling through calcium and changes in differentiation patterns when force generation is restricted.