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      Suppression of Kainate-Evoked AMPA Receptor Mediated Responses by Lanthanum in Rat Sacral Dorsal Commissural Neurons

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          Abstract

          The effect of lanthanum (La) on kainate (KA) responses in neurons acutely dissociated from the rat sacral dorsal commissural nucleus (SDCN) was investigated using the nystatin-perforated patch-recording configuration under voltage-clamp conditions. The responses to KA were mediated by activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in SDCN neurons. La<sup>3+</sup> reversibly inhibited KA (100 µ M) activated currents ( I<sub>KA</sub>) in a concentration-dependent manner over the range from 30 µ M to 30 m M, with IC<sub>50</sub> values of 0.64 ± 0.06 m M at a holding potential (V<sub>H</sub>) of –40 mV. Our further study indicated that the effects of La<sup>3+</sup> on I<sub>KA</sub> were voltage independent. Moreover, the inhibition was not use dependent and was not overcome by increasing the concentration of agonist. These findings indicate that La<sup>3+</sup> is an efficacious inhibitor of AMPA receptor mediated responses which may contribute to its cytotoxic effect.

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          Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors.

          N. Brown, J. Kerby, T Bonnert … (2002)
          1: The pharmacology of the stable cell line expressing human alpha(4)beta(3)delta GABA(A) receptor was investigated using whole-cell patch-clamp techniques. 2: alpha(4)beta(3)delta receptors exhibited increased sensitivity to GABA when compared to alpha(4)beta(3)gamma(2) receptors, with EC(50)'s of 0.50 (0.46, 0.53) microM and 2.6 (2.5, 2.6) microM respectively. Additionally, the GABA partial agonists piperidine-4-sulphonate (P4S) and 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridin-3-ol (THIP) displayed markedly higher efficacy at alpha(4)beta(3)delta receptors, indeed THIP demonstrated greater efficacy than GABA at these receptors. 3: The delta subunit conferred slow desensitization to GABA, with rate constants of 4.8+/-0.5 s for alpha(4)beta(3)delta and 2.5+/-0.2 s for alpha(4)beta(3)gamma(2). However, both P4S and THIP demonstrated similar levels of desensitization on both receptor subtypes suggesting this effect is agonist specific. 4: alpha(4)beta(3)delta and alpha(4)beta(3)gamma(2) demonstrated equal sensitivity to inhibition by the cation zinc (2-3 microM IC(50)). However, alpha(4)beta(3)delta receptors demonstrated greater sensitivity to inhibition by lanthanum. The IC(50) for GABA antagonists SR-95531 and picrotoxin, was similar for alpha(4)beta(3)delta and alpha(4)beta(3)gamma(2). Likewise, inhibition was observed on both subtypes at high and low pH. 5: alpha(4)beta(3)delta receptors were insensitive to modulation by benzodiazepine ligands. In contrast Ro15-4513 and bretazenil potentiated GABA responses on alpha(4)beta(3)gamma(2) cells, and the inverse agonist DMCM showed allosteric inhibition of alpha(4)beta(3)gamma(2) receptors. 6: The efficacy of neurosteroids at alpha(4)beta(3)delta receptors was greatly enhanced over that observed at alpha(4)beta(3)gamma(2) receptors. The greatest effect was observed using THDOC with 524+/-71.6% potentiation at alpha(4)beta(3)delta and 297.9+/-49.7% at alpha(4)beta(3)gamma(2) receptors. Inhibition by the steroid pregnenolone sulphate however, showed no subtype selectivity. The efficacy of both pentobarbitone and propofol was slightly augmented and etomidate greatly enhanced at alpha(4)beta(3)delta receptors versus alpha(4)beta(3)gamma(2) receptors. 7: We show that the alpha(4)beta(3)delta receptor has a distinct pharmacology and kinetic profile. With its restricted distribution within the brain and unique pharmacology this receptor may play an important role in the action of neurosteroids and anaesthetics. British Journal of Pharmacology (2002) 136, 965-974
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            The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related subunits.

            Anne Herb, Nail Burnashev, Pia Werner … (1992)
            A new ionotropic glutamate receptor subunit termed KA-2, cloned from rat brain cDNA, exhibits high affinity for [3H]kainate (KD approximately 15 nM). KA-2 mRNA is widely expressed in embryonic and adult brain. Homomeric KA-2 expression does not generate agonist-sensitive channels, but currents are observed when KA-2 is coexpressed with GluR5 or GluR6 subunits. Specifically, coexpression of GluR5(R) and KA-2 produces channel activity, whereas homomeric expression of either subunit does not. Currents through heteromeric GluR5(Q)/KA-2 channels show more rapid desensitization and different current-voltage relations when compared with GluR5(Q) currents. GluR6/KA-2 channels are gated by AMPA, which fails to gate homomeric GluR6 receptor channels. These results suggest possible in vivo partnership relations for high affinity kainate receptors.
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              GYKI 52466, a 2,3-benzodiazepine, is a highly selective, noncompetitive antagonist of AMPA/kainate receptor responses

              Michael Rogawski, Sean D. Donevan (1993)
              Article 0 comments Cited 9 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (publisher-id): NSG
                Journal ID (nlm-ta): Neurosignals
                Journal ID (doi): 10.1159/issn.1424-862X
                Title: Neurosignals
                Publisher: S. Karger AG
                ISSN (Print): 1424-862X
                ISSN (Electronic): 1424-8638
                Publication date Subscription-year: 2004
                Publication date (Print): October 2004
                Publication date (Electronic): 12 August 2004
                Volume: 13
                Issue: 5
                Pages: 258-264
                Affiliations
                aDepartment of Anatomy and K.K. Leung Brain Research Centre and bDepartment of Physiology, Fourth Military Medical University, Xi’an, China
                Article
                Publisher ID: 79340 Other ID: Neurosignals 2004;13:258–264
                DOI: 10.1159/000079340
                PubMed ID: 15305093
                SO-VID: ac227832-421f-458e-93ed-d0843ae672d8
                Copyright © © 2004 S. Karger AG, Basel
                License:

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Date received : 11 December 2003
                Date accepted : 04 May 2004
                Page count
                Figures: 4, References: 26, Pages: 7
                Categories
                Subject: Original Paper

                ScienceOpen disciplines: Geriatric medicine,Neurology,Cardiovascular Medicine,Neurosciences,Clinical Psychology & Psychiatry,Public health
                Keywords: Lanthanum,Kainate,Nystatin-perforated patch-clamp technique,α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor,Sacral dorsal commissural nucleus
                Data availability:
                ScienceOpen disciplines: Geriatric medicine, Neurology, Cardiovascular Medicine, Neurosciences, Clinical Psychology & Psychiatry, Public health
                Keywords: Lanthanum, Kainate, Nystatin-perforated patch-clamp technique, α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, Sacral dorsal commissural nucleus

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