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The Journal of Neuroscience, December 1, 2004, 24(48):10924-10940; doi:10.1523/JNEUROSCI.3424-04.2004

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Cellular/Molecular
Single-Channel Behavior of Heteromeric 1 Glycine Receptors: An Attempt to Detect a Conformational Change before the Channel Opens

Valeria Burzomato, Marco Beato, Paul J. Groot-Kormelink, David Colquhoun, and Lucia G. Sivilotti

Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom

The 1 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 1 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 (P_open) 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.

Key words: glycine; binding; gating; single channel; dose-response; patch clamp; kinetics

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Received Aug 19, 2004; revised October 18, 2004; accepted October 18, 2004.

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