Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iGluR5 induced by the high affinity agonist dysiherbaine and the functional antagonist 8,9-dideoxyneodysiherbaine

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iGluR5 induced by the high affinity agonist dysiherbaine and the functional antagonist 8,9-dideoxyneodysiherbaine. / Frydenvang, Karla Andrea; Lash, L Leanne; Naur, Peter; Postila, Pekka A; Pickering, Darryl S; Smith, Caleb M; Gajhede, Michael; Sasaki, Makoto; Sakai, Ryuichi; Pentikäinen, Olli T; Swanson, Geoffrey T; Kastrup, Jette Sandholm.

In: Journal of Biological Chemistry, Vol. 284, No. 21, 2009, p. 14219-14229.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Frydenvang, KA, Lash, LL, Naur, P, Postila, PA, Pickering, DS, Smith, CM, Gajhede, M, Sasaki, M, Sakai, R, Pentikäinen, OT, Swanson, GT & Kastrup, JS 2009, 'Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iGluR5 induced by the high affinity agonist dysiherbaine and the functional antagonist 8,9-dideoxyneodysiherbaine', Journal of Biological Chemistry, vol. 284, no. 21, pp. 14219-14229. https://doi.org/10.1074/jbc.M808547200

APA

Frydenvang, K. A., Lash, L. L., Naur, P., Postila, P. A., Pickering, D. S., Smith, C. M., ... Kastrup, J. S. (2009). Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iGluR5 induced by the high affinity agonist dysiherbaine and the functional antagonist 8,9-dideoxyneodysiherbaine. Journal of Biological Chemistry, 284(21), 14219-14229. https://doi.org/10.1074/jbc.M808547200

Vancouver

Frydenvang KA, Lash LL, Naur P, Postila PA, Pickering DS, Smith CM et al. Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iGluR5 induced by the high affinity agonist dysiherbaine and the functional antagonist 8,9-dideoxyneodysiherbaine. Journal of Biological Chemistry. 2009;284(21):14219-14229. https://doi.org/10.1074/jbc.M808547200

Author

Frydenvang, Karla Andrea ; Lash, L Leanne ; Naur, Peter ; Postila, Pekka A ; Pickering, Darryl S ; Smith, Caleb M ; Gajhede, Michael ; Sasaki, Makoto ; Sakai, Ryuichi ; Pentikäinen, Olli T ; Swanson, Geoffrey T ; Kastrup, Jette Sandholm. / Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iGluR5 induced by the high affinity agonist dysiherbaine and the functional antagonist 8,9-dideoxyneodysiherbaine. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 21. pp. 14219-14229.

Bibtex

@article{cdd728e02a6f11de9f0a000ea68e967b,
title = "Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iGluR5 induced by the high affinity agonist dysiherbaine and the functional antagonist 8,9-dideoxyneodysiherbaine",
abstract = "The prevailing structural model for ligand activation of ionotropic glutamate receptors posits that agonist efficacy arises from the stability and magnitude of induced domain closure in the ligand-binding core structure. Here we describe an exception to the correlation between ligand efficacy and domain closure. A weakly efficacious partial agonist of very low potency for homomeric iGluR5 kainate receptors, 8,9-dideoxy-neodysiherbaine (MSVIII-19), induced a fully closed iGluR5 ligand-binding core. The degree of relative domain closure, ~30 degrees , was similar to that we resolved with the structurally related high-affinity agonist dysiherbaine (DH), and to that of L-glutamate. The pharmacological activity of MSVIII-19 was confirmed in patch-clamp recordings from transfected HEK293 cells, where MSVIII-19 predominantly inhibits iGluR5-2a, with little activation apparent at a high concentration (1 mM) of MSVIII-19 (<1{\%} of mean glutamate-evoked currents). To determine the efficacy of the ligand quantitatively, we constructed concentration-response relationships for MSVIII-19 following potentiation of steady-state currents with concanavalin A (EC50 3.6 muM) and on the non-desensitizing receptor mutant iGluR5-2b(Y506C/L768C) (EC50 8.1 muM). MSVIII-19 exhibited a maximum of 16{\%} of full agonist efficacy as measured in parallel recordings with glutamate. Molecular dynamics simulations and electrophysiological recordings confirm that the specificity of MSVIII-19 for iGluR5 is partly attributable to inter-domain hydrogen bonds residues Glu441 and Ser721 in the iGluR5-S1S2 structure. The weaker interactions of MSVIII-19 with iGluR5 compared to DH, together with altered stability of the inter-domain interaction, may be responsible for the apparent uncoupling of domain closure and channel opening in this kainate receptor subunit.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Frydenvang, {Karla Andrea} and Lash, {L Leanne} and Peter Naur and Postila, {Pekka A} and Pickering, {Darryl S} and Smith, {Caleb M} and Michael Gajhede and Makoto Sasaki and Ryuichi Sakai and Pentik{\"a}inen, {Olli T} and Swanson, {Geoffrey T} and Kastrup, {Jette Sandholm}",
year = "2009",
doi = "10.1074/jbc.M808547200",
language = "English",
volume = "284",
pages = "14219--14229",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "21",

}

RIS

TY - JOUR

T1 - Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iGluR5 induced by the high affinity agonist dysiherbaine and the functional antagonist 8,9-dideoxyneodysiherbaine

AU - Frydenvang, Karla Andrea

AU - Lash, L Leanne

AU - Naur, Peter

AU - Postila, Pekka A

AU - Pickering, Darryl S

AU - Smith, Caleb M

AU - Gajhede, Michael

AU - Sasaki, Makoto

AU - Sakai, Ryuichi

AU - Pentikäinen, Olli T

AU - Swanson, Geoffrey T

AU - Kastrup, Jette Sandholm

PY - 2009

Y1 - 2009

N2 - The prevailing structural model for ligand activation of ionotropic glutamate receptors posits that agonist efficacy arises from the stability and magnitude of induced domain closure in the ligand-binding core structure. Here we describe an exception to the correlation between ligand efficacy and domain closure. A weakly efficacious partial agonist of very low potency for homomeric iGluR5 kainate receptors, 8,9-dideoxy-neodysiherbaine (MSVIII-19), induced a fully closed iGluR5 ligand-binding core. The degree of relative domain closure, ~30 degrees , was similar to that we resolved with the structurally related high-affinity agonist dysiherbaine (DH), and to that of L-glutamate. The pharmacological activity of MSVIII-19 was confirmed in patch-clamp recordings from transfected HEK293 cells, where MSVIII-19 predominantly inhibits iGluR5-2a, with little activation apparent at a high concentration (1 mM) of MSVIII-19 (<1% of mean glutamate-evoked currents). To determine the efficacy of the ligand quantitatively, we constructed concentration-response relationships for MSVIII-19 following potentiation of steady-state currents with concanavalin A (EC50 3.6 muM) and on the non-desensitizing receptor mutant iGluR5-2b(Y506C/L768C) (EC50 8.1 muM). MSVIII-19 exhibited a maximum of 16% of full agonist efficacy as measured in parallel recordings with glutamate. Molecular dynamics simulations and electrophysiological recordings confirm that the specificity of MSVIII-19 for iGluR5 is partly attributable to inter-domain hydrogen bonds residues Glu441 and Ser721 in the iGluR5-S1S2 structure. The weaker interactions of MSVIII-19 with iGluR5 compared to DH, together with altered stability of the inter-domain interaction, may be responsible for the apparent uncoupling of domain closure and channel opening in this kainate receptor subunit.

AB - The prevailing structural model for ligand activation of ionotropic glutamate receptors posits that agonist efficacy arises from the stability and magnitude of induced domain closure in the ligand-binding core structure. Here we describe an exception to the correlation between ligand efficacy and domain closure. A weakly efficacious partial agonist of very low potency for homomeric iGluR5 kainate receptors, 8,9-dideoxy-neodysiherbaine (MSVIII-19), induced a fully closed iGluR5 ligand-binding core. The degree of relative domain closure, ~30 degrees , was similar to that we resolved with the structurally related high-affinity agonist dysiherbaine (DH), and to that of L-glutamate. The pharmacological activity of MSVIII-19 was confirmed in patch-clamp recordings from transfected HEK293 cells, where MSVIII-19 predominantly inhibits iGluR5-2a, with little activation apparent at a high concentration (1 mM) of MSVIII-19 (<1% of mean glutamate-evoked currents). To determine the efficacy of the ligand quantitatively, we constructed concentration-response relationships for MSVIII-19 following potentiation of steady-state currents with concanavalin A (EC50 3.6 muM) and on the non-desensitizing receptor mutant iGluR5-2b(Y506C/L768C) (EC50 8.1 muM). MSVIII-19 exhibited a maximum of 16% of full agonist efficacy as measured in parallel recordings with glutamate. Molecular dynamics simulations and electrophysiological recordings confirm that the specificity of MSVIII-19 for iGluR5 is partly attributable to inter-domain hydrogen bonds residues Glu441 and Ser721 in the iGluR5-S1S2 structure. The weaker interactions of MSVIII-19 with iGluR5 compared to DH, together with altered stability of the inter-domain interaction, may be responsible for the apparent uncoupling of domain closure and channel opening in this kainate receptor subunit.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1074/jbc.M808547200

DO - 10.1074/jbc.M808547200

M3 - Journal article

C2 - 19297335

VL - 284

SP - 14219

EP - 14229

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 21

ER -

ID: 11859094