Authors' Names

Jill FarnsworthFollow

Presentation Type

Poster Presentation

Area of Focus

Life Sciences

Abstract

Glutamate receptors in the brain mediate fast excitatory signaling between neurons. The NMDA receptor (NMDAR) is a glutamate receptor subtype that plays key roles in learning and memory. In addition to L-glutamate (L-Glu), activation of NMDARs require binding of a co-agonist, either L-glycine (L-Gly) or D-serine (D-Ser). In the mammalian brain, D-Ser is synthesized from the more common L-enantiomer by the enzyme serine racemase (SR). Accumulating evidence suggests that D-Ser is the predominant co-agonist at synaptic NMDARs. However, the mechanisms that regulate levels of D-ser in the extracellular space are not fully understood. ASCT1 and ASCT2 are sodium-dependent neutral amino acid transporters that belong to the solute carrier 1 (SLC1) gene family. Many details regarding the cellular localization and functional roles of these transporters in the central nervous system are unknown. In this study we found that, in addition to broad recognition of many neutral L- amino acids, both ASCT1 and ASCT2 selectively transport D-Ser with Km values in the 100µM range. This result is in contrast to previous reports in the literature and suggests that these transporters may play an important role in influencing D-serine concentrations in the brain through uptake or exchange-mediated release. To further elucidate the factors that modulate D-ser levels in the brain, we have synthesized and characterized the properties of a novel ASCT1/2 blocker that inhibits transport through both transporters at nanomolar concentrations. Dysfunction of NMDA receptors has been associated with a number of neurodegenerative disorders including traumatic brain injury, stroke, and schizophrenia and this novel ASCT1/2 blocker and its analogs could prove to be therapeutically relevant for these and other conditions.

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Apr 18th, 2:30 PM Apr 18th, 3:50 PM

Identification of human SLC1 transporters that mediate transmembrane flux of D-serine

UC South Ballroom

Glutamate receptors in the brain mediate fast excitatory signaling between neurons. The NMDA receptor (NMDAR) is a glutamate receptor subtype that plays key roles in learning and memory. In addition to L-glutamate (L-Glu), activation of NMDARs require binding of a co-agonist, either L-glycine (L-Gly) or D-serine (D-Ser). In the mammalian brain, D-Ser is synthesized from the more common L-enantiomer by the enzyme serine racemase (SR). Accumulating evidence suggests that D-Ser is the predominant co-agonist at synaptic NMDARs. However, the mechanisms that regulate levels of D-ser in the extracellular space are not fully understood. ASCT1 and ASCT2 are sodium-dependent neutral amino acid transporters that belong to the solute carrier 1 (SLC1) gene family. Many details regarding the cellular localization and functional roles of these transporters in the central nervous system are unknown. In this study we found that, in addition to broad recognition of many neutral L- amino acids, both ASCT1 and ASCT2 selectively transport D-Ser with Km values in the 100µM range. This result is in contrast to previous reports in the literature and suggests that these transporters may play an important role in influencing D-serine concentrations in the brain through uptake or exchange-mediated release. To further elucidate the factors that modulate D-ser levels in the brain, we have synthesized and characterized the properties of a novel ASCT1/2 blocker that inhibits transport through both transporters at nanomolar concentrations. Dysfunction of NMDA receptors has been associated with a number of neurodegenerative disorders including traumatic brain injury, stroke, and schizophrenia and this novel ASCT1/2 blocker and its analogs could prove to be therapeutically relevant for these and other conditions.