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.

Dargan, S., Clarke, V., Alushin, G., Sherwood, J., Nistico', R.g., Bortolotto, Z., et al. (2009). ACET is a highly potent and specific kainate receptor antagonist: Characterisation and effects on hippocampal mossy fibre function. NEUROPHARMACOLOGY, 56(1), 121-130 [10.1016/j.neuropharm.2008.08.016].

ACET is a highly potent and specific kainate receptor antagonist: Characterisation and effects on hippocampal mossy fibre function

NISTICO', ROBERT GIOVANNI;
2009-01-01

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.
2009
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/14 - FARMACOLOGIA
English
Action Potentials; Alanine; Animals; Calcium; Cell Line, Transformed; Crystallography, X-Ray; Dose-Response Relationship, Drug; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Hippocampus; Humans; In Vitro Techniques; Models, Molecular; Mossy Fibers, Hippocampal; Pyramidal Cells; Rats; Receptors, Kainic Acid; Synaptic Transmission; Transfection; Uracil
Dargan, S., Clarke, V., Alushin, G., Sherwood, J., Nistico', R.g., Bortolotto, Z., et al. (2009). ACET is a highly potent and specific kainate receptor antagonist: Characterisation and effects on hippocampal mossy fibre function. NEUROPHARMACOLOGY, 56(1), 121-130 [10.1016/j.neuropharm.2008.08.016].
Dargan, S; Clarke, V; Alushin, G; Sherwood, J; Nistico', Rg; Bortolotto, Z; Ogden, A; Bleakman, D; Doherty, A; Lodge, D; Mayer, M; Fitzjohn, S; Jane, ...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/133192
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