Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors
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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 journal › Journal article › Research › peer-review
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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 - Former Faculty of Pharmaceutical Sciences
U2 - 10.1523/JNEUROSCI.1509-11.2011
DO - 10.1523/JNEUROSCI.1509-11.2011
M3 - Journal article
C2 - 21795528
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