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Dissertation
Determination of therapeutic potential and molecular mechanisms for allosteric modulators of glutamate transporters
Doctor of Philosophy (Ph.D.), Drexel University
May 2025
DOI:
https://doi.org/10.17918/00010922
Abstract
Excitatory Amino Acid Transporters (EAATs) are critical regulators of homeostatic glutamate levels in the central nervous system (CNS), and their dysfunction is implicated in several neuropsychiatric and neurological diseases. Our previous studies identified a library of small molecule compounds that modulate the activity of EAATs. These compounds exhibit various mechanisms, including positive and negative allosteric modulation (PAM and NAM, respectively), with distinct selectivity for EAAT subtypes. Given the critical role of glutamate in reward and addiction, we investigated EAAT2 modulation in a rodent model of cocaine use disorder. We demonstrated that administration of NA-014, an EAAT2 PAM, reduced cocaine-associated behaviors in rats in a sex-dependent manner. We also evaluated NA-014 and some analogs in primary neuron-glia cultures subjected to glutamate and oxygen glucose deprivation (OGD) insults, considering the role of glutamate excitotoxicity in ischemic stroke. NA-014 exhibited neuroprotective effects in both insult models, whereas NA-010, a selective EAAT2 NAM, did not. These findings support EAAT2 PAMs as a potential therapeutic approach for stroke, which currently lacks adequate treatments. Additionally, we characterized compounds from this library using mutagenesis and pharmacological approaches. We identified important molecular determinants of EAAT2 that are crucial for the activity of these compounds. Ten key amino acid residues within a subdomain of EAAT2 conferred EAAT2-selective PAM activity to EAAT1, revealing that these residues are sufficient to enhance activity. Collectively, these studies advanced our understanding of EAAT allosteric modulation and the therapeutic potential of EAAT2 PAMs.
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Details
- Title
- Determination of therapeutic potential and molecular mechanisms for allosteric modulators of glutamate transporters
- Creators
- Katelyn Louise Reeb
- Contributors
- Andreia Mortensen (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 181 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991022051052404721