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 articlepeer-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 articlepeer-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., Gajhede, M., Sasaki, M., Sakai, R., Pentikäinen, O. T., Swanson, G. T., & 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