Photoswitchable Inhibitor of a Glutamate Transporter

Bichu Cheng, Denis Shchepakin, Michael P. Kavanaugh, Dirk Trauner

Research output: Contribution to journalArticle

Abstract

Excitatory amino acid transporters clear glutamate from the synaptic cleft and play a critical role in glutamatergic neurotransmission. Their differential roles in astrocytes, microglia, and neurons are poorly understood due in part to a lack of pharmacological tools that can be targeted to specific cells and tissues. We now describe a photoswitchable inhibitor, termed ATT, that interacts with the major mammalian forebrain transporters EAAT1-3 in a manner that can be reversibly switched between trans (high-affinity) and cis (low-affinity) configurations using light of different colors. In the dark, ATT competitively inhibited the predominant glial transporter EAAT2 with ∼200-fold selectivity over the neuronal transporter EAAT3. Brief exposure to 350 nm light reduced the steady-state blocker affinity by more than an order of magnitude. Illumination of EAAT2 complexed with ATT induced a corresponding increase in the blocker off-rate monitored in the presence of glutamate. ATT can be used to reversibly manipulate glutamate transporter activity with light and may be useful to gain insights into the dynamic physiological roles of glutamate transporters in the brain, as well as to study the molecular interactions of transporters with ligands.

Original languageEnglish (US)
Pages (from-to)1668-1672
Number of pages5
JournalACS Chemical Neuroscience
Volume8
Issue number8
DOIs
StatePublished - Aug 16 2017

Keywords

  • Photopharmacology
  • TBOA
  • glutamate
  • neurotransmitter transporters EAAT

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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  • Cite this

    Cheng, B., Shchepakin, D., Kavanaugh, M. P., & Trauner, D. (2017). Photoswitchable Inhibitor of a Glutamate Transporter. ACS Chemical Neuroscience, 8(8), 1668-1672. https://doi.org/10.1021/acschemneuro.7b00072