Identification of Cadmium as a Structural and Functional Modulator of PSD-95 Regulating NMDARs at Postsynaptic Membranes

Author

Claudia Garza, The University of Texas Rio Grande Valley

Date of Award

5-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Yonghong Zhang

Second Advisor

Megan Keniry

Third Advisor

Xiaoqian Fang

Abstract

Postsynaptic density-95 (PSD-95) is an essential scaffolding protein in excitatory neurons. PSD-95’s N-terminal palmitoylation region elicits synaptic plasticity by targeting, anchoring, and trafficking glutamate receptors, such as N-methyl-d-aspartate receptors (NMDAR), to the postsynaptic membrane. The molecular interactions of PSD-95 and its dysregulation in excitatory synapses are currently being explored as primary causes of neurodegenerative diseases and disorders, such as Alzheimer’s disease, Schizophrenia, and Parkinson’s disease. Recent studies demonstrate an overaccumulation of zinc at two cysteines (C3 and C5) and two histidines (H24 and H28) of PSD-95 blocks palmitoylation, causing a loss of NMDAR at the postsynaptic membrane. In addition, exposure to heavy metals, such as cadmium, also demonstrates neurotoxic effects and accelerates cognitive impairment. This study investigates the interaction of cadmium with the N-terminal domain of PSD-95 and its effect on the regulatory function of PSD-95 on NMDARs through biochemical and computational methods. To identify an interaction between PSD-95 and cadmium, recombinant PSD-95 proteins were expressed in E. coli and purified by column chromatography for titration with cadmium. PSD-95 was also expressed in human embryonic kidney 293 (HEK293) cells to assess the palmitoylation of PSD-95 using acyl-biotinyl exchange (ABE) method. Our data showed HEK293 cells treated with 0.5 mM of CdCl2 for 5 min decreased PSD-95 palmitoylation. The results aid in illustrating how the strength of excitatory synapse transmission, postsynaptic plasticity, and palmitoylation is influenced by cadmium binding. The study reveals cadmium as a novel modulator for PSD-95 postsynaptic membrane association by chelating its N-terminal region and disrupting postsynaptic signaling. The findings of this study can advance the current knowledge and understanding of regulatory mechanisms of NMDA receptors at postsynaptic synapses to help identify prevention and treatment methods for neurodegenerative diseases and conditions.

Comments

Copyright 2025 Claudia Garza. https://proquest.com/docview/3240609458

Recommended Citation

Garza, C. (2025). Identification of Cadmium as a Structural and Functional Modulator of PSD-95 Regulating NMDARs at Postsynaptic Membranes [Master's thesis, The University of Texas Rio Grande Valley]. ScholarWorks @ UTRGV. https://scholarworks.utrgv.edu/etd/1681