2QS3

Crystal structure of the GluR5 ligand binding core dimer in complex with UBP316 at 1.76 Angstroms resolution

Summary for 2QS3

• Entry DOI: 10.2210/pdb2qs3/pdb
• Related: 1TXF 2F34 2F35 2F36 2QS1 2QS2 2QS4
• Descriptor: Glutamate receptor, ionotropic kainate 1, CHLORIDE ION, PENTAETHYLENE GLYCOL, ... (5 entities in total)
• Functional Keywords: membrane protein, cell junction, glycoprotein, ion transport, ionic channel, phosphorylation, postsynaptic cell membrane, receptor, rna editing, synapse, transmembrane, transport
• Biological source: Rattus norvegicus (rat); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P22756
• Total number of polymer chains: 2
• Total formula weight: 59829.42

Authors

Alushin, G.M.,Jane, D.E.,Mayer, M.L. (deposition date: 2007-07-30, release date: 2008-08-05, Last modification date: 2023-08-30)

Primary citation

Dargan, S.L.,Clarke, V.R.,Alushin, G.M.,Sherwood, J.L.,Nistico, R.,Bortolotto, Z.A.,Ogden, A.M.,Bleakman, D.,Doherty, A.J.,Lodge, D.,Mayer, M.L.,Fitzjohn, S.M.,Jane, D.E.,Collingridge, G.L.
ACET is a highly potent and specific kainate receptor antagonist: characterisation and effects on hippocampal mossy fibre function.
Neuropharmacology, 56:121-130, 2009

PubMed Abstract: 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.

PubMed: 18789344
DOI: 10.1016/j.neuropharm.2008.08.016

Experimental method

X-RAY DIFFRACTION (1.76 Å)