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Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors

Research output: Contribution to journalJournal articleResearchpeer-review

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Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors. / Harpsøe, Kasper; Ahring, Philip K; Christensen, Jeppe K; Jensen, Marianne L; Peters, Dan; Balle, Thomas.

In: Journal of Neuroscience, Vol. 31, No. 30, 27.07.2011, p. 10759-10766.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Harpsøe, K, Ahring, PK, Christensen, JK, Jensen, ML, Peters, D & Balle, T 2011, 'Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors' Journal of Neuroscience, vol. 31, no. 30, pp. 10759-10766. https://doi.org/10.1523/JNEUROSCI.1509-11.2011

APA

Harpsøe, K., Ahring, P. K., Christensen, J. K., Jensen, M. L., Peters, D., & Balle, T. (2011). Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors. Journal of Neuroscience, 31(30), 10759-10766. https://doi.org/10.1523/JNEUROSCI.1509-11.2011

Vancouver

Harpsøe K, Ahring PK, Christensen JK, Jensen ML, Peters D, Balle T. Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors. Journal of Neuroscience. 2011 Jul 27;31(30):10759-10766. https://doi.org/10.1523/JNEUROSCI.1509-11.2011

Author

Harpsøe, Kasper ; Ahring, Philip K ; Christensen, Jeppe K ; Jensen, Marianne L ; Peters, Dan ; Balle, Thomas. / Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 30. pp. 10759-10766.

Bibtex

@article{cce4301435444844a1a13fe7eb750e81,
title = "Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors",
abstract = "The neuronal a4{\ss}2 nicotinic acetylcholine receptors exist as two distinct subtypes, (a4)(2)({\ss}2)(3) and (a4)(3)({\ss}2)(2), and biphasic responses to acetylcholine and other agonists have been ascribed previously to coexistence of these two receptor subtypes. We offer a novel and radical explanation for the observation of two distinct agonist sensitivities. Using different expression ratios of mammalian a4 and {\ss}2 subunits and concatenated constructs, we demonstrate that a biphasic response is an intrinsic functional property of the (a4)(3)({\ss}2)(2) receptor. In addition to two high-sensitivity sites at a4{\ss}2 interfaces, the (a4)(3)({\ss}2)(2) receptor contains a third low-sensitivity agonist binding site in the a4a4 interface. Occupation of this site is required for full activation and is responsible for the widened dynamic response range of this receptor subtype. By site-directed mutagenesis, we show that three residues, which differ between the a4{\ss}2 and a4a4 sites, control agonist sensitivity. The results presented here provide a basic insight into the function of pentameric ligand-gated ion channels, which enables modulation of the receptors with hitherto unseen precision; it becomes possible to rationally design therapeutics targeting subpopulations of specific receptor subtypes.",
keywords = "The Faculty of Pharmaceutical Sciences",
author = "Kasper Harps{\o}e and Ahring, {Philip K} and Christensen, {Jeppe K} and Jensen, {Marianne L} and Dan Peters and Thomas Balle",
year = "2011",
month = "7",
day = "27",
doi = "10.1523/JNEUROSCI.1509-11.2011",
language = "English",
volume = "31",
pages = "10759--10766",
journal = "The Journal of neuroscience : the official journal of the Society for Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "30",

}

RIS

TY - JOUR

T1 - Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors

AU - Harpsøe, Kasper

AU - Ahring, Philip K

AU - Christensen, Jeppe K

AU - Jensen, Marianne L

AU - Peters, Dan

AU - Balle, Thomas

PY - 2011/7/27

Y1 - 2011/7/27

N2 - The neuronal a4ß2 nicotinic acetylcholine receptors exist as two distinct subtypes, (a4)(2)(ß2)(3) and (a4)(3)(ß2)(2), and biphasic responses to acetylcholine and other agonists have been ascribed previously to coexistence of these two receptor subtypes. We offer a novel and radical explanation for the observation of two distinct agonist sensitivities. Using different expression ratios of mammalian a4 and ß2 subunits and concatenated constructs, we demonstrate that a biphasic response is an intrinsic functional property of the (a4)(3)(ß2)(2) receptor. In addition to two high-sensitivity sites at a4ß2 interfaces, the (a4)(3)(ß2)(2) receptor contains a third low-sensitivity agonist binding site in the a4a4 interface. Occupation of this site is required for full activation and is responsible for the widened dynamic response range of this receptor subtype. By site-directed mutagenesis, we show that three residues, which differ between the a4ß2 and a4a4 sites, control agonist sensitivity. The results presented here provide a basic insight into the function of pentameric ligand-gated ion channels, which enables modulation of the receptors with hitherto unseen precision; it becomes possible to rationally design therapeutics targeting subpopulations of specific receptor subtypes.

AB - The neuronal a4ß2 nicotinic acetylcholine receptors exist as two distinct subtypes, (a4)(2)(ß2)(3) and (a4)(3)(ß2)(2), and biphasic responses to acetylcholine and other agonists have been ascribed previously to coexistence of these two receptor subtypes. We offer a novel and radical explanation for the observation of two distinct agonist sensitivities. Using different expression ratios of mammalian a4 and ß2 subunits and concatenated constructs, we demonstrate that a biphasic response is an intrinsic functional property of the (a4)(3)(ß2)(2) receptor. In addition to two high-sensitivity sites at a4ß2 interfaces, the (a4)(3)(ß2)(2) receptor contains a third low-sensitivity agonist binding site in the a4a4 interface. Occupation of this site is required for full activation and is responsible for the widened dynamic response range of this receptor subtype. By site-directed mutagenesis, we show that three residues, which differ between the a4ß2 and a4a4 sites, control agonist sensitivity. The results presented here provide a basic insight into the function of pentameric ligand-gated ion channels, which enables modulation of the receptors with hitherto unseen precision; it becomes possible to rationally design therapeutics targeting subpopulations of specific receptor subtypes.

KW - The Faculty of Pharmaceutical Sciences

U2 - 10.1523/JNEUROSCI.1509-11.2011

DO - 10.1523/JNEUROSCI.1509-11.2011

M3 - Journal article

VL - 31

SP - 10759

EP - 10766

JO - The Journal of neuroscience : the official journal of the Society for Neuroscience

JF - The Journal of neuroscience : the official journal of the Society for Neuroscience

SN - 0270-6474

IS - 30

ER -

ID: 33803256