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PDBsum entry 2qs3
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Membrane protein
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PDB id
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2qs3
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References listed in PDB file
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Key reference
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Title
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Acet is a highly potent and specific kainate receptor antagonist: characterisation and effects on hippocampal mossy fibre function.
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Authors
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S.L.Dargan,
V.R.Clarke,
G.M.Alushin,
J.L.Sherwood,
R.Nisticò,
Z.A.Bortolotto,
A.M.Ogden,
D.Bleakman,
A.J.Doherty,
D.Lodge,
M.L.Mayer,
S.M.Fitzjohn,
D.E.Jane,
G.L.Collingridge.
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Ref.
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Neuropharmacology, 2009,
56,
121-130.
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PubMed id
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Abstract
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Kainate receptors (KARs) are involved in both NMDA receptor-independent
long-term potentiation (LTP) and synaptic facilitation at mossy fibre synapses
in the CA3 region of the hippocampus. However, the identity of the KAR subtypes
involved remains controversial. Here we used a highly potent and selective GluK1
(formerly GluR5) antagonist (ACET) to elucidate roles of GluK1-containing KARs
in these synaptic processes. We confirmed that ACET is an extremely potent GluK1
antagonist, with a Kb value of 1.4+/-0.2 nM. In contrast, ACET was ineffective
at GluK2 (formerly GluR6) receptors at all concentrations tested (up to 100
microM) and had no effect at GluK3 (formerly GluR7) when tested at 1 microM. The
X-ray crystal structure of ACET bound to the ligand binding core of GluK1 was
similar to the UBP310-GluK1 complex. In the CA1 region of hippocampal slices,
ACET was effective at blocking the depression of both fEPSPs and
monosynaptically evoked GABAergic transmission induced by ATPA, a GluK1
selective agonist. In the CA3 region of the hippocampus, ACET blocked the
induction of NMDA receptor-independent mossy fibre LTP. To directly investigate
the role of pre-synaptic GluK1-containing KARs we combined patch-clamp
electrophysiology and 2-photon microscopy to image Ca2+ dynamics in individual
giant mossy fibre boutons. ACET consistently reduced short-term facilitation of
pre-synaptic calcium transients induced by 5 action potentials evoked at
20-25Hz. Taken together our data provide further evidence for a physiological
role of GluK1-containing KARs in synaptic facilitation and LTP induction at
mossy fibre-CA3 synapses.
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