TY - JOUR
T1 - Photoswitchable Inhibitor of a Glutamate Transporter
AU - Cheng, Bichu
AU - Shchepakin, Denis
AU - Kavanaugh, Michael P.
AU - Trauner, Dirk
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/8/16
Y1 - 2017/8/16
N2 - 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.
AB - 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.
KW - Photopharmacology
KW - TBOA
KW - glutamate
KW - neurotransmitter transporters EAAT
UR - http://www.scopus.com/inward/record.url?scp=85027402934&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.7b00072
DO - 10.1021/acschemneuro.7b00072
M3 - Article
C2 - 28414419
AN - SCOPUS:85027402934
SN - 1948-7193
VL - 8
SP - 1668
EP - 1672
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 8
ER -