Burzomato, V.;
Beato, M.;
Groot-Kormelink, P.J.;
Colquhoun, D.;
Sivilotti, L.G.;
(2004)
Single-channel behavior of heteromeric α1β glycine receptors: an attempt to detect a conformational change before the channel opens.
Journal of Neuroscience
, 24
(48)
pp. 10924-10940.
10.1523/JNEUROSCI.3424-04.2004.
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Abstract
The α1β heteromeric receptors are likely to be the predominant synaptic form of glycine receptors in the adult. Their activation mechanism was investigated by fitting putative mechanisms to single-channel recordings obtained at four glycine concentrations (10-1000 µM) from rat {alpha}1{beta} receptors, expressed in human embryonic kidney 293 cells. The adequacy of each mechanism, with its fitted rate constants, was assessed by comparing experimental dwell time distributions, open-shut correlations, and the concentration-open probability (Popen) curve with the predictions of the model. A good description was obtained only if the mechanism had three glycine binding sites, allowed both partially and fully liganded openings, and predicted the presence of open-shut correlations. A strong feature of the data was the appearance of an increase in binding affinity as more glycine molecules bind, before the channel opens. One interpretation of this positive binding cooperativity is that binding sites interact, each site sensing the state of ligation of the others. An alternative, and novel, explanation is that agonist binding stabilizes a higher affinity form of the receptor that is produced by a conformational change ("flip") that is separate from, and precedes, channel opening. Both the "interaction" scheme and the flip scheme describe our data well, but the latter has fewer free parameters and above all it offers a mechanism for the affinity increase. Distinguishing between the two mechanisms will be important for our understanding of the structural dynamics of activation in the nicotinic superfamily and is important for our understanding of mutations in these receptors.
| Type: | Article |
|---|---|
| Title: | Single-channel behavior of heteromeric α1β glycine receptors: an attempt to detect a conformational change before the channel opens |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1523/JNEUROSCI.3424-04.2004 |
| Publisher version: | http://dx.doi.org/10.1523/JNEUROSCI.3424-04.2004 |
| Language: | English |
| Additional information: | Published by the Society of Neuroscience This work is licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. The license allows you to copy, distribute, and transmit the work, as well as adapting it. However, you must attribute the work to the author (but not in any way that suggests that they endorse you or your use of the work), and cannot use the work for commercial purposes without prior permission of the author. If you alter or build upon this work, you can distribute the resulting work only under the same or similar license to this one. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ or send a letter to Creative Commons, 444 Castro Street, Suite 900, Mountain View, California, 94041, USA. |
| Keywords: | Glycine, binding, gating, single channel, dose-response, patch clamp, kinetics |
| URI: | https://discovery.ucl.ac.uk/id/eprint/9776 |
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