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Photoswitchable Inhibitor of a Glutamate Transporter.
Cheng, Bichu; Shchepakin, Denis; Kavanaugh, Michael P; Trauner, Dirk.
Afiliación
  • Cheng B; Department of Chemistry and Center for Integrated Protein Science (CIPSM), LMU Munich , 81377 Munich, Germany.
  • Shchepakin D; University of Montana Center for Neuroscience , 32 Campus Drive, Missoula, Montana 59803, United States.
  • Kavanaugh MP; University of Montana Center for Neuroscience , 32 Campus Drive, Missoula, Montana 59803, United States.
  • Trauner D; Department of Chemistry and Center for Integrated Protein Science (CIPSM), LMU Munich , 81377 Munich, Germany.
ACS Chem Neurosci ; 8(8): 1668-1672, 2017 08 16.
Article en En | MEDLINE | ID: mdl-28414419
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Ácido Aspártico / Transportador 1 de Aminoácidos Excitadores / Proteínas de Transporte de Glutamato en la Membrana Plasmática / Transportador 3 de Aminoácidos Excitadores / Moduladores del Transporte de Membrana Límite: Animals / Humans Idioma: En Revista: ACS Chem Neurosci Año: 2017 Tipo del documento: Article País de afiliación: Alemania

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Ácido Aspártico / Transportador 1 de Aminoácidos Excitadores / Proteínas de Transporte de Glutamato en la Membrana Plasmática / Transportador 3 de Aminoácidos Excitadores / Moduladores del Transporte de Membrana Límite: Animals / Humans Idioma: En Revista: ACS Chem Neurosci Año: 2017 Tipo del documento: Article País de afiliación: Alemania