{"id":10,"date":"2011-03-10T20:59:08","date_gmt":"2011-03-10T20:59:08","guid":{"rendered":"https:\/\/onemol.org.uk\/?page_id=10"},"modified":"2025-08-16T11:26:32","modified_gmt":"2025-08-16T11:26:32","slug":"10-2","status":"publish","type":"page","link":"https:\/\/onemol.org.uk\/?page_id=10","title":{"rendered":"Publications"},"content":{"rendered":"\n<p><a href=\"#follow\"><span class=\"smallprint\">Jump to follow-up<\/span><\/a><\/p>\n\n\n\n<p>Some of our main papers since 2003 are listed below, with commentaries and reprints. Some older papers and classics can be&nbsp;<a href=\"https:\/\/onemol.org.uk\/?page_id=10#hist\">downloaded here too.<\/a><\/p>\n\n\n\n<p>.For more papers, follow these links.<\/p>\n\n\n\n<p><strong>Lucia Sivilotti<\/strong>\u2018s papers are listed also on her&nbsp;<a href=\"http:\/\/www.ucl.ac.uk\/npp\/ls.html\" target=\"_blank\" rel=\"noopener noreferrer\">UCL home page<\/a>. and on Lucia Sivilotti&#8217;s profile on <a href=\"http:\/\/scholar.google.co.uk\/citations?user=u4h0IMAAAAAJ&amp;hl=en\" target=\"_blank\" rel=\"noopener noreferrer\">Google scholar<\/a>.<\/p>\n\n\n\n<p><strong>David Colquhoun<\/strong>\u2018s papers are listed below and on the <a href=\"https:\/\/onemol.org.uk\/?page_id=175\" target=\"_blank\" rel=\"noopener noreferrer\">theory papers page<\/a>.See also David Colquhoun&#8217;s profile on <a href=\"http:\/\/scholar.google.co.uk\/citations?user=JXQ2kXoAAAAJ&amp;hl=en\" target=\"_blank\" rel=\"noopener noreferrer\">Google scholar<\/a>.<br>Some may still be on&nbsp;<a href=\"http:\/\/www.ucl.ac.uk\/Pharmacology\/dc-bits\/dcpubs.html\" target=\"_blank\" rel=\"noopener noreferrer\">old UCL page<\/a>&nbsp;(some with reprints) and&nbsp;<a href=\"http:\/\/www.ucl.ac.uk\/Pharmacology\/dc-bits\/chpapers.html\" target=\"_blank\" rel=\"noopener noreferrer\">older papers here<\/a>.<\/p>\n\n\n\n<p>For fun, you may also like&nbsp;<a href=\"http:\/\/www.dcscience.net\/\" target=\"_blank\" rel=\"noopener noreferrer\">DC\u2019s Improbable Science blog<\/a>, and&nbsp;<a href=\"http:\/\/www.ucl.ac.uk\/Pharmacology\/dc-bits\/dcpics.html\" target=\"_blank\" rel=\"noopener noreferrer\">photo pages<\/a>.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\">Some recent papers with commentary and reprints<\/h3>\n\n\n\n<p><a id=\"hc2024\" name=\"hc2024\"><\/a><\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>James P. Higham and David Colquhoun (2024)<\/strong> The affinity\u2013efficacy problem: an essential part of pharmacology education. <i>R. Soc. Open Sci. 11<\/i>: 240487. <a href=\"https:\/\/doi.org\/10.1098\/rsos.240487\" target=\"_blank\" rel=\"noreferrer noopener\">doi.org\/10.1098\/rsos.240487<\/a> <br>\n<a href=\"https:\/\/royalsocietypublishing.org\/doi\/10.1098\/rsos.240487\" target=\"_blank\" rel=\"noreferrer noopener\">Link to full text (open access)<\/a>  <br><em><span style=\"color: #800000;\"> A review of the ideas of affinity and efficacy.  There is nothing new in it, but it was motivated by the fact that these topics are still very often misunderstood by students, their teachers and by IUPHAR.  The <a href=\"https:\/\/rs.figshare.com\/articles\/journal_contribution\/Derivations_and_numerical_examples_of_the_equations_discussed_in_Sections_2_and_3_from_The_affinity-efficacy_problem_an_essential_part_of_pharmacology_education\/26106099?backTo=%2Fcollections%2FSupplementary_material_from_The_affinity-efficacy_problem_an_essential_part_of_pharmacology_education_%2F7303143%3FbackTo%3D%2Fcollections%2FSupplementary_material_from_The_affinity-efficacy_problem_an_essential_part_of_pharmacology_education_%2F7303143&amp;file=47425944\" target=\"_blank\" rel=\"noreferrer noopener\">supplementary material<\/a> spells out the derivations in detail, and we hope that it will provide a useful resource for teachers.<br><\/span><\/em> [#hc2024]<\/li>\n<\/ul>\n\n\n<p><!-- \/wp:post-content --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a id=\"sbs2017\" name=\"sbs2017\"><\/a><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Safar, F., Hurdiss, E., Erotocritou, M., Greiner, T., Lape, R., Irvine, M.W., Fang, G., Jane, D., Yu, R., D\u00e4mgen, M.A., Biggin, P.C., Sivilotti L.G. (2017)<\/strong>, The startle disease mutation E103K impairs activation of human homomeric \u03b11 glycine receptors by disrupting an intersubunit salt bridge across the agonist binding site<em> Journal of Biological Chemistry<\/em>, <strong>292<\/strong>,5031-42 (2016) DOI: 10.1074\/jbc.M116.767616.<br \/>[<a href=\"https:\/\/onemol.org.uk\/Safar-J-Biol-Chem-2017-5031-42.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download pdf<\/a>].<br \/><em><span style=\"color: #800000;\"> Analysis of a mutation in the human glycine receptor, E103K, that causes startle disease. It is one of few startle disease mutations found in the extracellular agonist binding site of the channel, in loop A of the principal side of the subunit interface. Despite its position near the binding site, E103K causes hyperekplexia by impairing the efficacy of glycine, its ability to gate the channel once bound, rather than by changing the ability of glycine to bind.<br \/><\/span><\/em> [#sbs2017]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a id=\"ecgs2016\" name=\"ecgs2016\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Michael Epstein, Ben Calderhead, Mark A. Girolami, and Lucia G. Sivilotti (2016)<\/strong> Bayesian Statistical Inference in Ion-Channel Models with Exact Missed Event Correction. <em>Biophysical Journal<\/em> (2016). <a href=\"10.1085\/jgp.201611649\" target=\"_blank\" rel=\"noopener noreferrer\">http:\/\/dx.doi.org\/10.1016\/j.bpj.2016.04.053 <\/a> [<a href=\"https:\/\/onemol.org.uk\/Epstein-Bayesian-Biophys-J-2016.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download pdf<\/a>].<br \/><em><span style=\"color: #800000;\"> This is the first paper to implement a Bayesian analysis of single ion channel records which uses the exact missed event correction (as used in our <a href=\"https:\/\/onemol.org.uk\/?page_id=10#chh2003\" target=\"_blank\" rel=\"noopener noreferrer\">maximum likelihood program, HJCFIT<\/a>) [<a href=\"https:\/\/onemol.org.uk\/?page_id=8\" target=\"_blank\" rel=\"noopener noreferrer\">download HJCFIT<\/a>]. The prior distribution for each parameter (rate constant) is uniform over the physically-plausible range of values. In HJCFIT the parameter estimates are constrained to the same range, so the estimates of rate constants should be identical. In the case of well-defined parameters, the estimates are indeed much the same, and their errors (covariance matrix) are represented well by the covariance matrix found from the Hessian, in <a href=\"https:\/\/onemol.org.uk\/?page_id=10#chh2003\" target=\"_blank\" rel=\"noopener noreferrer\">HJCFIT<\/a>. But the posterior distribution of each parameter provides a way to look at the uncertainty in the ill-defined rate constants that occur in over-parameterised problems. The Biophysical Journal commissioned a<a href=\"https:\/\/onemol.org.uk\/Ball-on-Epstein-BJ-2016.pdf\" target=\"_blank\" rel=\"noopener noreferrer\"> commentary on this paper, by Frank Ball [download pdf]<\/a><br \/><\/span><\/em> [#ecgs2016]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"sc2016\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Lucia Sivilotti and David Colquhoun (2016)<\/strong> In Praise of Single Channel Kinetics. <em>Journal of General Physiology <\/em>(2016). <a href=\"10.1085\/jgp.201611649\" target=\"_blank\" rel=\"noopener noreferrer\">DOI: 10.1085\/jgp.201611649<\/a>\u00a0\u00a0\u00a0 [<a href=\"https:\/\/onemol.org.uk\/Sivilotti-Colquhoun-J-Gen-Physiol-2016.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download pdf<\/a>]. [<a href=\"http:\/\/jgp.rupress.org\/content\/148\/2\/79\" target=\"_blank\" rel=\"noopener noreferrer\">open access<\/a>]<br \/><em><span style=\"color: #800000;\"> This is a commentary on Mukhtasimova, N., C.J. daCosta, and S.M. Sine. 2016 Improved resolution of single channel dwell times reveals mechanisms of binding, priming, and gating in muscle AChR. <em>J.Gen. Physiol.<\/em> 148:43\u201363 (<a href=\"http:\/\/dx .doi .org \/10 .1085 \/jgp .201611584\" target=\"_blank\" rel=\"noopener noreferrer\">http :\/\/dx .doi .org \/10 .1085 \/jgp .201611584<\/a>)<br \/>The improved resolution confirms that the channel opening does not arise directly from the resting conformation, but rather from a short-lived pre-open shut conformation. It also confirms that partial agonists have essentially the same opening rate as full agonists, and that the origin of their low efficacy lies in the initial conformation changes, not in the shut-open conformation change. These conclusions are compatible with those of <a href=\"#vb-04\">Burzomato <em>et al<\/em><\/a>., (2004) and with <a href=\"https:\/\/onemol.org.uk\/?page_id=10#lcs-08\" target=\"_blank\" rel=\"noopener noreferrer\">Lape <em>et al.<\/em>. (2008)<\/a>. The major difference from earlier work lies in the postulation of negative cooperativity in the two bindings to the resting conformation, which has not been needed before. This problem is discussed.<br \/><\/span><\/em> [#sc2016]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"mls2015\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Alessandro Marabelli, Remigijus Lape, and Lucia Sivilotti (2015)<\/strong>Mechanism of activation of the prokaryotic channel ELIC by propylamine: A single-channel study<em>Journal of General Physiology <\/em> (2015) <strong>145<\/strong>, 23\u201345<br \/><a href=\"http:\/\/www.jgp.org\/cgi\/doi\/10.1085\/jgp.201411234\" target=\"_blank\" rel=\"noopener noreferrer\">www.jgp.org\/cgi\/doi\/10.1085\/jgp.201411234 <\/a>\u00a0\u00a0\u00a0 [<a href=\"https:\/\/onemol.org.uk\/Marabelli-J Gen Physiol-2015-23-45.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download pdf<\/a>].<br \/><em><span style=\"color: #800000;\"> A single channel study of the prokaryotic channel from Erwinia chrysanthemi (ELIC). This channel has a high conductance and its structure is better known than that of the related eukaryotic channels such as the glycine and nicotinic receptors. The results could not be fitted well with the Flipped model, but were well-described by the Primed model.<br \/><\/span><\/em> [#mls2015]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"yu14\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Rilei Yu, Eliott Hurdiss, Timo Greiner, Remigijus Lape, Lucia Sivilotti and Philip C. Biggin<br \/>(2015)<\/strong> Agonist and Antagonist Binding in Human Glycine Receptors<br \/>. <em>Biochemistry<\/em> 53, 6041\u22126051 (2014). dx.doi.org\/10.1021\/bi500815f<br \/>[<a href=\"\/Yu-Hurdiss-Greiner-Lape-Sivilotti-Biggin-Biocchemistry-2015.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download pdf<\/a>].<br \/><em><span style=\"color: #800000;\"> An investigation of the binding of glycine by molecular dynamics, using a homology model of the human glycine receptor. The results cast new light on the glycine binding site. Simulation of the binding of the antagonist, strychnine, suggests the strychnine binding induces movement to a conformational state that is distinct from the glycine-bound or apo state, not only within the ligand-binding domain but also in the transmembrane domain. This implies that strychnine is not just a passive competitive antagonist, but produces effects of its own.<br \/><\/span><\/em>\u00a0\u00a0[#yu14]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"zmbsd12\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Zimmermann I, Marabelli A, Bertozzi C, Sivilotti LG, Dutzler R (2012)<\/strong> Inhibition of the Prokaryotic Pentameric Ligand-Gated Ion Channel ELIC by Divalent Cations. <em>PLoS Biol<\/em> 10(11): e1001429. doi:10.1371\/journal.pbio.1001429 [<a href=\"Zimmermann-2013.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download pdf<\/a>].\u00a0\u00a0[<a href=\"Zimmermann-2013-supplementary.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download supplementary info<\/a>]<br \/><em><span style=\"color: #800000;\"> An investigation the effect of divalent ions on ELIC, a prokaryotic pentameric homologut if ligand gated ion channels with known structure. Divalent cations inhibit the activation of ELIC by the agonist cysteamine,<br \/>reducing both its potency and, at higher concentrations, its maximum response. X-ray crystallography was used to locate the binding site for divalent cations is located at the outer rim of the extracellular domain, at the interface between adjacent subunits, at some distance from the agonist binding region.<\/span><\/em>\u00a0\u00a0[#zmbsd12]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"cl2012\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>David Colquhoun and Remigijus Lape(2012)<\/strong>. Allosteric coupling in ligand-gated ion channels. <em>Journal of General Physiology<\/em> <strong>140<\/strong>, :599\u00a0\u2013\u00a0612. [<a href=\"Colquhoun-&amp;-Lape-JGP-2012.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download pdf<\/a>].<br \/><em><span style=\"color: #800000;\">Our contribution to a series of Perspectives on: Conformational coupling in ion channels. It is argued that the word &#8220;allosteric&#8221; is too ambiguous to be useful as a description of mechanism. When it is possible to estimate all the rate constants in a specified reaction mechanism, such descriptions become redundant. Topics discussed include microscopic reversibility and the preferred routes from shut to open.<\/span><\/em> \u00a0\u00a0 [#cl2012]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"lape2012\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong><a href=\"https:\/\/iris.ucl.ac.uk\/research\/personal\/index?upi=RLAPE20\" target=\"_blank\" rel=\"noopener noreferrer\">Remigijus Lape<\/a>, <a href=\"http:\/\/fmp-berlin.info\/research\/signal-transduction-molecular-g\/profile-signaltransduction\/mnb\/mnb-home.html\" target=\"_blank\" rel=\"noopener noreferrer\">Andrew J. R. Plested<\/a>, Mirko Moroni, David Colquhoun,and <a href=\"http:\/\/www.ucl.ac.uk\/npp\/research\/ls\" target=\"_blank\" rel=\"noopener noreferrer\">Lucia G. Sivilotti<\/a> (2012)<\/strong>. The \u03b11K276E Startle Disease Mutation Reveals Multiple Intermediate States in the Gating of Glycine Receptors<em> Journal of Neuroscience<\/em>. <strong>32(4)<\/strong>, :1336\u00a0\u2013\u00a01352. [<a href=\"Lape-2012-K276E.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download pdf<\/a>]. <em><span style=\"color: #800000;\"><br \/>In human glycine receptors the \u03b11K276E mutation causes hyperekplexia, a rare inherited disease associated with an exaggerated startle response. It took us quite a long time to work out the mechanistic reason for the loss of function in the mutant receptor. It is interesting to us, because it is the first case we&#8217;ve encountered in which our flip model has failed to provide an adequate description of the observations. The &#8220;flip&#8221; mechanism was introduced in <a href=\"#vb-04\">Burzomato <em>et al<\/em> 2004<\/a>, for alpha1-containing glycine receptors and found also to fit nicotinic acetylcholine receptors by <a href=\"https:\/\/onemol.org.uk\/?page_id=10#lcs-08\" target=\"_blank\" rel=\"noopener noreferrer\">Lape <em>et al<\/em>., 2008<\/a>, who also showed that it provided an elegant description of partial agonism. It was obvious from the start that the flip model would not describe channels which open spontaneously and that a generalisation of it, like the &#8220;primed&#8221; model, would be needed (<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/19339970\" target=\"_blank\" rel=\"noopener noreferrer\">Muhktasimova <em>et al.<\/em><\/a>, <em>Nature<\/em> <strong>459<\/strong>, 451, 2009). In the case of the \u03b11K276E the results were too complicated to be fitted by the flip model, but the more general primed model fitted well.<br \/><\/span><\/em> \u00a0\u00a0[#lape2012]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"krashia2011\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Paraskevi Krashia, Remigijus Lape, Francesco Lodesani, David Colquhoun, and Lucia G. Sivilotti (2011)<\/strong>. The long activations of alpha2 glycine channels can be described by a mechanism with reaction intermediates (\u201cflip\u201d)<em> Journal of General Physiology<\/em>. <strong>137<\/strong>, 197\u00a0\u2013\u00a0216. [<a href=\"krashia-et-al-2011.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download reprint<\/a>].<br \/><em><span style=\"color: #800000;\">Our flip model survives another test. The &#8220;flip&#8221; mechanism was introduced in <a href=\"#vb-04\">Burzomato <em>et al<\/em> 2004<\/a>, for alpha1-containing glycine receptors and found also to fit nicotinic acetylcholine receptors by <a href=\"https:\/\/onemol.org.uk\/?page_id=10#lcs-08\" target=\"_blank\" rel=\"noopener noreferrer\">Lape <em>et al<\/em>., 2008<\/a>, who also showed that it provided an elegant description of partial agonism. This paper is about a very different glycine receptor, the homomeric alpha2 receptor. At first the flip model did not seem to describe the results, but after we realised that the very long groups of openings seen at low concentrations of glycine were actually single very long activations of the channel, everything fell in to place. The flip model provides also an elegant mechanistic description of the very long shut times between activations. <\/span><\/em> \u00a0\u00a0 [#krashia2011]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"moroni2011\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Mirko Moroni, Istvan Biro, Michele Giugliano, Ranjit Vijayan, Philip C. Biggin and Lucia G. Sivilotti (2011)<\/strong>. Chloride ions in the pore of glycine and GABA channels shape the time course and voltage dependence of agonist currents <em> Journal of Neuroscience<\/em>. <strong>31<\/strong>, 14095\u00a0\u2013\u00a014106. [<a href=\"Moroni 2011 chloride.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download reprint<\/a>].<br \/><em><span style=\"color: #800000;\">We show that glycine and GABA receptors &#8220;sense&#8221; chloride concentrations because of interactions between the M2 pore-lining domain and the permeating ions. This interaction is complex and must involve a site with asymmetrical access from the two sides of the membrane, because high extracellular chloride can slow deactivation, but only if intracellular chloride is low (4 mM). The sensitivity of channel gating to chloride is abolished if the channel is mutated to become cation selective. The appropriate interaction between permeating ions and channel pore is also necessary to maintain the channel voltage sensitivity of gating. <\/span><\/em> \u00a0\u00a0 [#moroni2011]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"lgs2010\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Sivilotti LG (2010)<\/strong>. What single channel analysis tells us of the activation mechanism of ligand-gated channels: the case of the glycine receptor. <em>J Physiol <\/em>2010; 588:45-58. [<a href=\"sivilotti-2010.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download reprint<\/a>][#lgs2010]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"lkcs2009\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Remigijus Lape, Paraskevi Krashia, David Colquhoun and Lucia G. Sivilotti (2009)<\/strong>\u00a0 Agonist and blocking actions of choline<br \/>and tetramethylammonium on human muscle acetylcholine receptors.<em>Journal of Physiology<\/em>. <strong>587<\/strong>, 5045\u00a0\u2013\u00a05072. [<a href=\"Lape-Krashia-Colquhoun-Sivilotti-JPhys-2009.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download reprint<\/a>].<br \/><em><span style=\"color: #800000;\">Choline has been widely used as a very weak agonist iun studies of gain-of-function mutants.\u00a0 It is very hard to study because it blocks ion channels at concentrations lower than those needed to activate the channel, so it has taken a while to get enough results,\u00a0 The single channel results can be fitted on the hypothesis that choline is actually a full agonist and its reposnse is limited bu channel block rather than partial agonism.\u00a0 However concentration jump experiments (as well as the feeling that it is likely to be quailitatively like TMA) favour the alternative idea that choline is a very weak agonist because it is very inefficient at producing the intermediate pre-open &#8216;flipped&#8217; conformation of the receptor.\u00a0 Once flipped, the channel can open and shut with similar rates to those found with acetylcholine and TMA.\u00a0\u00a0 This interpretation is consistent with our earlier work in <a href=\"#vb-04\">Burzomato et al 2004<\/a>), and in <a href=\"https:\/\/onemol.org.uk\/?page_id=10#lcs-08\" target=\"_blank\" rel=\"noopener noreferrer\">Lape et al., 2008<\/a>.<br \/><\/span><\/em> \u00a0\u00a0[#lkcs2009]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"lcs2008\"><\/a><br \/><a name=\"lcs-08\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Remigijus Lape, David Colquhoun &amp; Lucia Sivilotti (2008)<\/strong>\u00a0 On the nature of partial agonism in the nicotinic receptor superfamily (2008).<em>Nature<\/em>. <strong>454<\/strong>, 722 &#8211;\u00a0728. [<a href=\"lape-colquhoun-sivilotti-nature-2008.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Download reprint<\/a>, or <a href=\"lape-colquhoun-sivilotti-all-2008.zip\" target=\"_blank\" rel=\"noopener noreferrer\">zip file with movie<\/a>]<br \/><em><span style=\"color: #800000;\">This paper is the culmination of three years&#8217; work. For 50 years, ever since del Castillo &amp; Katz (1957), it has been assumed that partial agonists will be deficient in producing the open-shut reaction.\u00a0 In this paper we find, for both glycine and nicotinic receptors, that opening and shutting of the channel is very much the same for partial and full agonists. The deficiency in partial agonists lies earlier, in the production of the pre-open &#8216;flip&#8217; state (first identified in <a href=\"#vb-04\">Burzomato et al 2004<\/a>). <\/span><\/em><br \/><em><span style=\"color: #800000;\">See also items about this paper on <a href=\"http:\/\/www.ucl.ac.uk\/news\/news-articles\/0807\/08072101\" target=\"_blank\" rel=\"noopener noreferrer\">UCL News<\/a>, the <a href=\"news-and-views-08.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">News and Views<\/a> in <em>Nature<\/em> and <a href=\"makingthepaper-08.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Making the paper<\/a> in <em>Nature<\/em>.<\/span><\/em> \u00a0\u00a0[#lcs-08]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- wp:list-item --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul>\n<li><strong>Pitt, S, Sivilotti, LG &amp; Beato, M. (2008)<\/strong> High intracellular chloride slows the decay of glycinergic currents.<em>J.Neuroscience<\/em> 28, 11454-67. [<a href=\"pitt-sivilotti-beato-JN-2008.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download reprint<\/a>].<br \/><em><span style=\"color: #800000;\">Synaptic-like currents produced by concentration-jumps of glycine onto outside-out patches were at least 3-fold slower than expected from the results of our kinetic model fitted to cell-attached data.\u00a0 This discrepancy is due to different recording solutions for the two configurations and not to a difference between native and recombinant channels.\u00a0 High symmetrical chloride is often used especially in neurons to enhance recorded inhibitory synaptic currents, but it distorts them by making them much slower.\u00a0 By recording synaptic currents from motoneurones before and after raising their intracellular chloride, we show that this effect is important also in slice recordings. \u00a0We have since shown that a similar phenomenon occurs for GABAA channels<\/span><\/em><\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- wp:list-item --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul>\n<li><strong>Beato, M. &amp; Sivilotti, L.G. (2007)<\/strong> Single-channels properties of glycine receptors of juvenile rat spinal motoneurones in vitro.<em> J.Physiol,<\/em> 580, 497-506. [<a href=\"beato-sivilotti-JPhys-2007.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download reprint<\/a>]<br \/><em><span style=\"color: #800000;\">The conductance of these native glycine channels in cell-attached patches shows that they are likely to be heteromers.\u00a0 In addition to that, native channels have kinetic properties similar to those of recombinant a1b channels: their fast and effective gating can be described by the \u2018flip \u2019mechanism of Burzomato et al., 2004.\u00a0\u00a0 <\/span><\/em><\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"A52S-2007\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Plested, A., Groot-Kormelink, P., Colquhoun, D. &amp; Sivilotti, L.G. (2007)<\/strong> Single channel study of the spasmodic mutation \u03b11 A52S in recombinant rat glycine receptors. <em>J.Physiol<\/em>., 581, 51-73. see accompanying Perspective by J.H. Steinbach, <em>J.Physiol.<\/em>, 581,3 [<a href=\"plested07.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download reprint<\/a>] [<a href=\"steinbach-on-plested-07.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download perspective<\/a>]<br \/><em><span style=\"color: #800000;\">Inherited defects in glycine receptors produce hyperekplexia, or startle disease. A mutant mouse, spasmodic, that has a startle phenotype, has a point mutation (A52S) in the glycine receptor \u03b11 subunit.\u00a0 The results could be fitted with our flip mechanism (Burzomato et al. 2004). \u00a0The reduction in affinity for the flipped conformation accounts for the reduction in apparent cooperativity seen in the mutant receptor (without having to postulate interaction between the binding sites) and it accounts for the decreased potency of glycine on mutant receptors. This mechanism also predicts accurately the faster decay of synaptic currents that is observed in spasmodic mice.<\/span><\/em> [#A52S-2007]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- wp:list-item --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul>\n<li>\u00a0<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- wp:list-item --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul>\n<li><strong>Beato, M., Burzomato, V. &amp; Sivilotti, L.G. (2007)<\/strong> The kinetics of inhibition of rat recombinant heteromeric \u03b11\u03b2 glycine receptors by the low affinity antagonist SR-95531.<em> <em>J.Physiol,<\/em><\/em> 580: 171-179. [<a href=\"Beato-Burzomato-Sivilotti-JPhys-2007.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download reprint<\/a>]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"schild2007\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Colquhoun, D (2007)<\/strong>\u00a0 Why the Schild method is better than Schild realised <em>Trends in Pharmacological Sciences<\/em>, <strong>28<\/strong>, 608 &#8211; 614.[<a href=\"colquhoun-schild-tips-2007.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download reprint<\/a>].<em><span style=\"color: #800000;\">The Schild method allows genuine physical equilibrium constants for competitive antagonists to be obtained from experiments in which complex responses are measured.\u00a0 This paper extends work done in 1973 (<a href=\"http:\/\/www.ucl.ac.uk\/Pharmacology\/dc-bits\/chpapers.html#dc73\">here<\/a>), and gives conditions under which valid results can be obtained. The Schild method may still be valid with multiple agonist binding sites, even when agonist binding sites interact and\/or are not identical. \u00a0\u00a0[#schild2007]<\/span><\/em><em><br \/><\/em><\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- wp:list-item --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul>\n<li><strong>Groot-Kormelink, P., Broadbent, S, Beato, M. &amp; Sivilotti, L.G. (2006)<\/strong> Constraining the expression of nicotinic acetylcholine receptors using pentameric constructs.\u00a0 <em>Mol. Pharm.,<\/em> 69, 558-63; see Perspective in \u00a0<em>Mol Pharm.<\/em> 69, 407-10. [<a href=\"PJK-SB-MB-LGS-Mol-Pharm-2006b.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download reprint<\/a>] [<a href=\"White-perspective-mol-pharm-2006.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download Perspective<\/a>]<br \/><em><span style=\"color: #800000;\">An alternative approach that is more effective in constraining receptor composition than the tandem + monomer formula is to produce pentameric constructs.\u00a0 This paper shows a first characterization of their properties.<\/span><\/em><\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- wp:list-item --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul>\n<li><strong>Broadbent, S., Groot-Kormelink, P., Krashia, P., Harkness, P.,Millar, N., Beato, M. &amp; Sivilotti, L.G.(2006)<\/strong> Incorporation of the beta3 subunit has a dominant negative effect on the function of recombinant central-type neuronal nicotinic receptors.\u00a0 <em>Mol Pharm,<\/em> 70, 1350-7. [<a href=\"Broadbent-LGS-Mol-Pharm-2006a.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download reprint<\/a>]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"tips2006\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Colquhoun, D. (2006).<\/strong>The quantitative analysis of drug\u2013receptor interactions: a short history. <em>Trends in Pharmacological Sciences<\/em>, <strong>27<\/strong>, 149 &#8211; 157.<br \/><em><span style=\"color: #800000;\">A short history of what&#8217;s often called &#8216;receptor theory. It&#8217;s surprising that almost every major player has had a connection with UCL.<\/span> <\/em>[<a href=\"https:\/\/onemol.org.uk\/Colquhoun-TiPS-History-2006.pdf\" target=\"_blank\" rel=\"noopener\">download pdf<\/a>]<br \/>#tips2006<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"ss05\"><\/a><br \/><a name=\"ss2005\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Schorge, S., Elenes, S. &amp; Colquhoun, D. (2005)<\/strong>. Maximum likelihood fitting of single channel NMDA activity with a mechanism composed of independent dimers of subunits <i>Journal of Physiology<\/i><b> 569<\/b>, 395 \u2013 418. <a href=\"schorge-05.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">[Download reprint 5.9Mb]<\/a><em><span style=\"color: #800000;\">Our best shot at kinetic analysis of an NMDA receptor. We find an opening rate for the channel that is much faster than that found by other labs, probably because our analysis methods can detect fast shut times (see Fig. 11).<\/span><\/em>\u00a0\u00a0[#ss05]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"vb-04\"><\/a><br \/><a name=\"vb2004\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Burzomato, V., Beato, M., Groot-Kormelink, P., Colquhoun, D. &amp; Sivilotti, L.G. (2004)<\/strong> Single-channel behavior of heteromeric alpha1beta glycine receptors: An attempt to detect a conformational change before the channel opens <em>J.Neuroscience<\/em>, 24, 10924-10940. [<a href=\"burzomato-2004.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download reprint<\/a>]<br \/><em><span style=\"color: #800000;\">In heteromeric glycine channels (found in adult synapses), the three glycine binding sites appear to interact, i.e. there is a progressive increase in the channel affinity for glycine as more molecules bind. This apparent interaction may be explained by a conformational change that takes place upon binding, but while the channel is still closed (\u2018flip\u2019 mechanism). This is the first time that a reaction intermediate has been identified and it represents the first qualitative advance in reaction mechanisms since the classic work of Castillo &amp; Katz, over 50 years ago. The basic idea has now been confirmed in the USA (Muhktasimova et al, <em>Nature<\/em> 459, 451, 2009). It was exploited by us to reinterpret the action of partial agonists (see <a href=\"https:\/\/onemol.org.uk\/?page_id=10#lcs-08\" target=\"_blank\" rel=\"noopener noreferrer\">Lape et al. 2008<\/a>).<\/span><\/em> \u00a0\u00a0[#vb-04]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"impact2003\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Colquhoun, D. ( 2003)<\/strong> Challenging the tyranny of impact factors <i>Nature<\/i> <b>423<\/b>, 479.<br \/><a href=\"nature-impact-2003.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">[Get PDF]<\/a> \u00a0\u00a0[#impact2003]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"bkobit2003\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li>Professor Sir Bernard Katz. <i>Biophysicist who arrived in England with \u00a34 and went on to win a Nobel Prize<\/i> (Obituary) <i>Independent<\/i> 26 April 2003<a href=\"bkobit.pdf\"> [Get PDF]<\/a> or reproduction of <a href=\"bkobit-scan.pdf\">Newspaper version<\/a> \u00a0\u00a0[#bkobit2003]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- wp:list-item --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul>\n<li>Professor Sir Bernard Katz. A longer account of his life from <i>Physiology News<\/i> (Autumn 2003, number 52, pp 34\u201338) <a href=\"bk-phys-soc-news.pdf\" target=\"_blank\" rel=\"noopener noreferrer\"> [Get PDF]<\/a>Inside front cover (portrait) <a href=\"inside_front_cover.pdf\" target=\"_blank\" rel=\"noopener noreferrer\"> [Get PDF]<\/a>Inside back cover (scenes from BK&#8217;s life) <a href=\"inside_back_cover.pdf\" target=\"_blank\" rel=\"noopener noreferrer\"> [Get PDF]<\/a><\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"chh2003\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Colquhoun, D., Hatton, C., &amp; Hawkes, A. G. ( 2003)<\/strong> The quality of maximum likelihood estimation of ion channel rate constants . <i>Journal of Physiology (London) <\/i> <b>547<\/b>, 699\u2013728. <a href=\"c-hatton-hawkes-03.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">[Get PDF]<\/a><br \/><i><span style=\"color: #800000;\">A study of the ability of the HJCFIT method to extract rate constants for a reaction mechanism from a sequence of open and shut times. our analysis was applied to a large number of &#8216;experiments&#8217; that were generated by simulation, so the true values for the rate constants were known. Sampling distributions are shown for the fitted parameters. HJCFIT is the only fitting method that has been tested in this way.<\/span><\/i> \u00a0\u00a0 [#chh2003]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"hsbbc2003\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Hatton, C., Shelley, C., Brydson, M., Beeson, D., &amp; Colquhoun, D. ( 2003)<\/strong> Properties of the human muscle nicotinic receptor, and of the slow\u2013channel syndrome mutant <span style=\"font-family: symbol;\">e<\/span>L221F, inferred from maximum likelihood fits. <i>Journal of Physiology (London)<\/i> <b>547<\/b>, 729-760. <a href=\"hatton-shelley-bb-and-c-03.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">[Get PDF]<\/a><i><span style=\"color: #800000;\">Application of the HJCFIT method to wild type nicotinic receptors, and to a disease\u2013causing mutant.<\/span><\/i> \u00a0\u00a0 [#hsbbc2003]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Colquhoun, D., Unwin, N., Shelley, C., Hatton, C. J., &amp; <a href=\"http:\/\/www.ucl.ac.uk\/Pharmacology\/Research\/ls.html\">Sivilotti, L.<\/a> ( 2003)<\/strong> Nicotinic Acetylcholine Receptors. Abrahams, D. 6th Edition, Vol 2: Drug Discovery and Drug Development, Chapter 11, 357\u2013405. New York, John Wiley. Burger&#8217;s Medicinal Chemistry.<br \/><a href=\"medchem-review-03.pdf\" target=\"_blank\" rel=\"noopener noreferrer\"> [Get PDF]<\/a><br \/><i><span style=\"color: #800000;\">A review of the relationship between structure and function in nicotinic receptors.<\/span><\/i>\u00a0\u00a0\u00a0[#cushs03]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"sc03\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>Schorge, S. &amp; Colquhoun, D. (2003).<\/strong> Studies of NMDA receptor function and stoichiometry with truncated and tandem subunits. <i>Journal of Neuroscience<\/i><b> 23, <\/b>1151\u20131158 <a href=\"schorge-c-03.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">[Get PDF]<\/a><br \/><i><span style=\"color: #800000;\">A study with tandem constructs. The results suggest that the order of the subunits in NMDA receptor is NR1\u2013NR1\u2013NR2\u2013NR2, perhaps because it is a dimer made of one NR1 dimer and and NR2 dimer.<\/span><\/i>\u00a0\u00a0\u00a0[#sc03]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"bcw99\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:list --><\/p>\n<ul>\n<li style=\"list-style-type: none;\">\n<ul><!-- wp:list-item -->\n<li><strong>B\u00e9h\u00e9, P,, Colquhoun, D. &amp; Wyllie, D.J.A. (1999)<\/strong>.\u00a0 \u00a0Activation of Single AMPA- and NMDA-Type Glutamate-Receptor Channels.\u00a0 Chapter 5 in: <em>Ionotropic glutamate receptors in the CNS, Handbook of Experimental Pharmacology<\/em> Volume 141, Eds: P. Jonas and H. Monyer, Springer-Verlag, Berlin, pp. 175-218.\u00a0 \u00a0 [<a href=\"https:\/\/onemol.org.uk\/Behe-Colquhoun-Wyllie-1999.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download pdf<\/a>]<br \/><i><span style=\"color: #800000;\">A review that contains results that have not been published elsewhere, particularly on the latency to first channel opening after a short jump in agonist concentration. We made the mistake of publishing it in a very expenSive book which isn&#8217;t available online. You can <a href=\"https:\/\/onemol.org.uk\/Behe-Colquhoun-Wyllie-1999.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">download it here<\/a>.<\/span><\/i> \u00a0\u00a0[#bcw99]<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p><!-- \/wp:list-item --><\/p>\n<p><!-- \/wp:list --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"bjp1998\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p>Some of the basic principles were laid out in a 1998 review<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><strong>Colquhoun, D.<\/strong> (1998). Binding, gating, affinity and efficacy. The interpretation of structure\u2013activity relationships for agonists and of the effects of mutating receptors\u00a0<em>British Journal of Pharmacology<\/em>\u00a0,\u00a0<strong>125<\/strong>,923\u2013948.\u00a0<a href=\"http:\/\/onemol.org.uk\/Colquhoun-1998-BJP-review.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">[Get PDF]<\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><em><span style=\"color: #800000;\">A review that attempts to bring together the classical pharmacological ideas of &#8216;affinity&#8217; and &#8216;efficacy&#8217;, with the &#8216;binding\u2013gating&#8217; problem that arises whenever binding of a ligand causes a conformation change in a protein .<\/span><\/em> \u00a0\u00a0 [#bjp1998] \n<a name=\"hist\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:heading {\"level\":3} --><\/p>\n<p><a name=\"bb1995\"><\/a><\/p>\n<h3 class=\"wp-block-heading\">Papers from the &#8216;Blue book&#8217;, <em>Single Channel Recording<\/em><\/h3> [#bb1995]\n<p><!-- \/wp:heading --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p>These are my most cited papers.\u00a0 \u00a0The three chapters that we contributed to this book (236 pages in all) describe methods for dealing with the theory and practice of single channel recording. All that&#8217;s missing is the fitting of mechanisms with exact allowance for missed events. For details of that, see <a href=\"https:\/\/onemol.org.uk\/?page_id=175#chs96\" target=\"_blank\" rel=\"noopener\">here<\/a>,\u00a0 <a href=\"#chh2003\">here<\/a>\u00a0 and <a href=\"#vb-04\" target=\"_blank\" rel=\"noopener\">here<\/a>.<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"cs1995\"><\/a><\/p>\n<p>\u00a0Colquhoun, D. &amp; Sigworth, F. J. (1995). Analysis of single ion channel data. Chapter 19 in <em>Single channel recording<\/em>, 2nd edition.\u00a0 Eds. Sakmann, B. &amp; Neher, E., pp. 483-587, Plenum Press, New York.\u00a0 [<a href=\"https:\/\/onemol.org.uk\/colquhoun-sigworth-1995_neher-sakmann_single-channel_rec_2nd_ed.pdf\" target=\"_blank\" rel=\"noopener\">Download pdf<\/a>]  [#cs1995]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><em><span style=\"color: #800000;\">This chapter describes methods for the idealisation and empirical fitting of single channel recordings.<\/span><\/em><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"ch1995a\"><\/a><\/p>\n<p>Colquhoun, D. &amp; Hawkes, A. G. (1995). The principles of the stochastic interpretation of ion channel mechanisms. Chapter 18 in <em>Single channel recording<\/em>,\u00a0 2nd edition.\u00a0 Eds. Sakmann, B. &amp; Neher, E., pp. 397-482, Plenum Press, New York. [<a href=\"https:\/\/onemol.org.uk\/colquhoun-hawkes-1995_neher-sakmann_single-channel_rec_2nd_ed.pdf\" target=\"_blank\" rel=\"noopener\">Download pdf<\/a>] [#ch1995a]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><em><span style=\"color: #800000;\">This chapter describes the stochastic theory that underlies the interpretation of single channel recordings in terms of any specified reaction mechanism.<\/span><\/em><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"ch1995b\"><\/a><\/p>\n<p>Colquhoun, D. &amp; Hawkes, A. G. (1995). A Q-matrix Cookbook. Chapter 20 in <em>Single channel recording<\/em>,\u00a0 2nd edition.\u00a0 Eds. Sakmann, B. &amp; Neher, E., pp. 589-633, Plenum Press, New York. [<a href=\"https:\/\/onemol.org.uk\/colquhoun-hawkes-qmatrix-1995_neher-sakmann_single-channel_rec_2nd_ed.pdf\" target=\"_blank\" rel=\"noopener\">download pdf<\/a>] [#ch1995b]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><em><span style=\"color: #800000;\">This chapter describes how to write a single computer program that will do the calculations for any specified reaction mechanism.<\/span><\/em><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:heading {\"level\":3} --><\/p>\n<h3 class=\"wp-block-heading\">Older papers<\/h3>\n<p><!-- \/wp:heading --><\/p>\n<p><!-- wp:heading {\"level\":3} --><\/p>\n<h3 class=\"wp-block-heading\">Some classical papers<\/h3>\n<p><!-- \/wp:heading --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"Hill1909\"><\/a><br \/>Hill,A.V. (1909) The mode of action of nicotine and curari determined by the form of the contraction curve and the method of temperature coefficients. <em>J. Physiol. (Lond)<\/em>, <strong>39<\/strong>, 361-373.\u00a0 [<a href=\"hill-1909.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Get pdf<\/a> (0.58 Mb)]<br \/><span style=\"color: #800000;\">This is A.V. Hill&#8217;s first paper. It describes the Langmuir equation (both rates and equilibrium) some time before Langmuir (1918) did so.<\/span> \u00a0\u00a0\u00a0[#Hill1909]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"jbsh1938\"><\/a><br \/>Haldane, J.B.S. (1930) <em>Enzymes<\/em>, Longmans, Green and Co.London.\u00a0 [<a href=\"haldane-enzymes-1930-s.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Get pdf<\/a> (0.31.Mb)]<br \/><span style=\"color: #800000;\">This is the section of Haldane&#8217;s book that describes mechanisms: Michaelis-Menten and Briggs-Haldane, and in particular the case of competitive inhibition (see pp 46-47 of book, pp 20-21 of pdf file).<\/span> \u00a0\u00a0\u00a0[#jbsh1938]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"dcold\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:heading {\"level\":3} --><\/p>\n<h3 class=\"wp-block-heading\">Older papers from DC lab<\/h3>\n<p><!-- \/wp:heading --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a href=\"http:\/\/www.jstor.org\/\">The JSTOR web site<\/a> now has in pdf format, in its <i><b>General Science Collection<\/b><\/i>, the entire contents of the <a href=\"http:\/\/www.royalsoc.ac.uk\/\"><i>Royal Society<\/i><\/a> journals back to the 17th century, <i>Proceedings of the National Academy of Sciences<\/i>, and of <i>Science<\/i>. The pdf files can be downloaded by any site that subscribes to JSTOR.<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p>Older papers from the Journal of Physiology are now available from the <a href=\"http:\/\/www.pubmedcentral.gov\/tocrender.fcgi?journal=236&amp;action=archive\">Pubmed central archive<\/a>, For example<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"cs85\"><\/a><br \/><strong>Colquhoun, D. &amp; Sakmann, B. (1985).<\/strong> Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate. <em>Journal of Physiology ( London ) <\/em><strong>369 <\/strong>, 501-557. <a href=\"colquhoun &amp; sakmann 1985.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">[Get pdf)]<\/a><br \/><span style=\"color: #800000;\"><em>See also the &#8216;classical perspective on this paper, written in 2007 (<a href=\"colquhoun-classical-perspective-2007.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">here<\/a>).<\/em><\/span> \u00a0\u00a0\u00a0[#cs85]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"goc84\"><\/a><br \/><strong>Gardner, P., Ogden, D.C. and Colquhoun, D. (1984)<\/strong> Conductances of single ion channels opened by nicotinic agonists are indistinguishable. Nature, 309, 160 &#8211; 162. <a href=\"Gardner Ogden &amp; Colquhoun 1984.pdf\">[Get PDF)]<\/a><br \/><span style=\"color: #800000;\"><em>This paper used single channel measurements to show that all the agonists were tested produced openings of virtually the same amplitude. It corrected <a href=\"#cdss77\">a 1975 paper<\/a> which had come to the opposite conclusion using noise analysis. This showed that the reason that some agonists are partial is not because they open channels of lower conductance than full agonists. The use of single channels made the measurements very simple, so it&#8217;s doubtful if this would have appeared in Nature if it were not for the fact that it corrected our earlier report. This was so obvious that when I walked into the common room in in G\u00f6ttingen, shortly after it came out, someone said &#8220;How did you get that into <em>Nature<\/em>, are you sleeping with <a href=\"http:\/\/www.nature.com\/nature\/journal\/v493\/n7430\/full\/493013b.html\" target=\"_blank\" rel=\"noopener noreferrer\">Maxine Clarke<\/a>?&#8221;.<\/em><\/span> \u00a0\u00a0\u00a0[#goc84]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"ch82\"><\/a><br \/><strong>Colquhoun, D. &amp; Hawkes, A.G. (1982)<\/strong> On the stochastic properties of bursts of single ion channel openings and of clusters of bursts.<i> Philosophical Transactions of the Royal Society London<\/i> <b>B 300<\/b>, 1-59. <a href=\"Colquhoun &amp; Hawkes-1982-ocr.pdf\">[Get PDF (2.6 Mb)]<\/a><br \/><span style=\"color: #800000;\"><em>This is the paper that describes the notation used in all subsequent papers, and uses it to obtain distributions of open and shut times, of burst properties, and the properties of clusters of bursts (it supersedes a theoretical paper written a year earlier, in 1981, which used a much clumsier notation). The equations derived here are elegant closed forms, but make no allowance for missed events. That did not become possible until 1990 &#8211; 1992.<\/em><\/span> \u00a0\u00a0\u00a0[#ch02]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"ch81\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><strong>Colquhoun, D. &amp; Sakmann, B.(1981) <\/strong>Fluctuations in the microsecond time range of the current through single acetylcholine receptor ion channels. <em>Nature<\/em> <strong>294<\/strong>, 464 &#8211; 466. <a title=\"_blank\" href=\"https:\/\/onemol.org.uk\/Colquhoun-&amp;-Sakmann-1981.pdf\">[Get PDF]<\/a><br \/><span style=\"color: #800000;\"><em>This is our first experimental single ion channel paper. It gives our first rough values for affinity and efficacy and it&#8217;s also the first description of the existence of a component of short openings which we attributed, tentatively, to brief openings of mono-liganded receptors.<\/em><\/span>\u00a0\u00a0\u00a0[#ch81]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"c81\"><\/a><br \/><strong>Colquhoun, D. (1981).<\/strong> How fast do drugs work? <em>\u00a0\u00a0Trends in Pharmacological Sciences<\/em> <strong>8<\/strong>, 212 \u2013 217 [<a title=\"934 kb\" href=\"colquhoun-1981-tips-how-fast.pdf\">Get pdf<\/a>]<br \/><span style=\"color: #800000;\"><em>This old paper is still sometimes found useful by students. It was written as an introduction to ideas about measuring the rates of reactions, as opposed to equilibrium constants. It therefore deals with macroscopic responses, noise analysis and single channels in an elementary way.<\/em><\/span><br \/>[#c81]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"cds79\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><strong>Colquhoun, D., Dreyer, F., &amp; Sheridan, R. E. (1979).<\/strong> The actions of tubocurarine at the frog neuromuscular junction. <em>Journal of Physiology (London)<\/em> <strong>293<\/strong>, 247-284. <a href=\"colquhoun-dreyer-sheridan-ocr-1979.pdf\">[Get PDF)]<\/a><span style=\"color: #800000;\"><br \/><em>This paper describes the very long lasting channel blockages&#8217; that can be produced by (+)-tubocurarine (in addition to its competitive action). Such long blockages would be hard to identify on single channel records so even if we had been able to measure them in 1977 -78, the voltage-jump method used here might still have been the best.<\/em><\/span> \u00a0\u00a0\u00a0[#cds79]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"ch77\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><strong>Colquhoun, D. &amp; Hawkes, A. G.<\/strong> (1977). Relaxation and fluctuations of membrane currents that flow through drug-operated channels. <i>Proceedings of the Royal Society London B<\/i> <b>199<\/b>, 231-262.<br \/>[<a href=\"Colquhoun &amp; Hawkes-1977-ocr.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Get pdf 2.6 Mb<\/a>]<br \/><span style=\"color: #800000;\"><em>This 1977 paper is the first of many papers written with Alan Hawkes. Its origin dates back to 1972 when I wrote to Alan Hawkes to ask how the noise analysis, recently published by Katz &amp; Miledi, could be generalised to any reaction mechanism. The theory predicted that the predominant time constant from noise analysis would be longer than the mean channel open time, for any realistic values of the rate constants. The physical meaning of this eluded us at first, but after being pressed by Bernard Katz to explain the result, we realised that it was a result of channel openings being predicted to not to occur singly, but in bursts. By the time the paper came out, Neher &amp; Sakmann&#8217;s 1976 paper had appeared and we were soon able to test the prediction.<\/em><\/span> \u00a0\u00a0\u00a0[#ch77]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"cdss75\"><\/a><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><strong>Colquhoun, D., Dionne, V. E., Steinbach, J. H. &amp; Stevens, C. F. (1975)<\/strong>. Conductance of channels opened by acetylcholine-like drugs in muscle end-plate. <em>Nature<\/em> 253, 204-206. [<a href=\"Colquhoun-Dionne-Steinbach-Stevens-1975.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Get pdf<\/a>]<br \/><span style=\"color: #800000;\"><em>In this paper we tested the hyopthesis that partial agonists produce a smaller maximum response than full antagonists because they open channels with lower conductance than full agonists. It was before the days when single channel measurements were possible so we used noise analysis. We found that partial agonists opened channels with smaller conductance than those elicited by full agonists. When we <a href=\"#goc84\">tested this again<\/a> with single channel measurements in 1984, this result was found to be wrong. Despite some careful calculations, the quality of the two-electrode voltage clamp at the frog endplate must have been lower than we thought. The partial agonist tended to have higher frequency components than full agonsits and some of the area under the power spectrum must have been lost.<\/em><\/span> \u00a0\u00a0\u00a0[#cdss75]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><strong>Colquhoun, D.(1970).<\/strong> How long does a molecule stay on the receptor? Explanation of a paradox.<em>\u00a0\u00a0 British Journal of Pharmacology<\/em> <strong>39<\/strong>, 215P [<a href=\"colquhoun-1970.pdf\">Get PDF<\/a>]<br \/><span style=\"color: #800000;\"><em>This is the abstract of a talk given at the 1969 meeting of the British Pharmacological Society. At the time I had just discovered, <em>via<\/em> Alan Hawkes, the waiting time paradox. This resolved, at a stroke, many of the problems that I&#8217;d been having in thinking about what happened at the level of a single drug-receptor complex.<\/em><\/span><\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<a name=\"dc69\"><\/a>\n<p><strong>Colquhoun, D. (1969)<\/strong>. A comparison of estimators for a two-parameter hyperbola. <i>Journal of Royal Statistical Society <\/i>C <b>1<\/b>8, 130-140. [<a href=\"colquhoun-lsfits-1969.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Get PDF (887 kb)]<\/a> ]<br \/><span style=\"color: #800000;\"><em>Another historical item: a study of the quality of estimates for a simple Langmuir equation by different methods of fitting, showing the best method is generally least squares. This was one of my first attempts at programming a real computer. The simulations were run on an <a href=\"http:\/\/www.youtube.com\/watch?v=8EKBNfm5B4U\" target=\"_blank\" rel=\"noopener noreferrer\">Elliott 803<\/a>, using <a href=\"http:\/\/en.wikipedia.org\/wiki\/ALGOL\" target=\"_blank\" rel=\"noopener noreferrer\">Algol<\/a>, on punched paper tape.<\/em> <\/span>    [#dc69]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<a name=\"dc68               \"><\/a>\n<p><strong>Colquhoun, D. (1968)<\/strong>. The rate of equilibration in a competitive <em>n<\/em> drug system and the auto-inhibitory equations of enzyme kinetics: some properties of simple models for passive sensitization. <em>Proceedings of the Royal Society<\/em>. <strong>B. 170<\/strong>, 135-154 [<a href=\"https:\/\/onemol.org.uk\/Colquhoun-1968.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Get PDF (2460 kb)]<\/a> ]<br \/><span style=\"color: #800000;\"><em>This was DC&#8217;s first published work to use matrix notation, for macroscopic (not single channel) kinetics. It provided a general way to look at the rate of approach to equilibrium in systems with n competing ligands. The results were applied to several models for passive sensitisation that were of interest at the time. Curve-fitting programs were written in <a href=\"http:\/\/en.wikipedia.org\/wiki\/ALGOL\" target=\"_blank\" rel=\"noopener noreferrer\">Algol<\/a>, for the University of London <a href=\"https:\/\/en.wikipedia.org\/wiki\/Atlas_(computer)\" target=\"_blank\" rel=\"noopener noreferrer\">Atlas computer<\/a><\/em> <\/span>    [#dc68]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:heading {\"level\":3} --><\/p>\n<h3 class=\"wp-block-heading\">Two older papers from books<\/h3>\n<p><!-- \/wp:heading --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p>These two papers have been scanned (because the books in which they appeared are now hard to find).<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"dc73\"><\/a> <strong>Colquhoun, D. (1973)<\/strong>. The relation between classical and cooperative models for drug action. In <em>Drug Receptors<\/em>, ed. Rang, H. P., pp. 149-182. Macmillan Press, London. [<a href=\"colquhoun-1973.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">Get pdf file: 4.04 Mb<\/a>]<br \/><i><span style=\"color: #800000;\">This paper attempted to reconcile the emerging knowledge of cooperativity in ion channel receptors with the more classical views. It showed that the Schild approach for competitive antagonists was indeed valid for a wide range of receptor mechanisms, but that agonists could give results that were incompatible with Stephenson&#8217;s ideas. But it failed to grasp completely the fatal error in the classical approach, The approach to the Schild plot was updated and generalised <a href=\"colquhoun-schild-tips-2007.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">in 2007<\/a>.<\/span> <\/i> \u00a0\u00a0\u00a0[#dc73]<\/p>\n<p><!-- \/wp:paragraph --><\/p>\n<p><!-- wp:paragraph --><\/p>\n<p><a name=\"dc87\"><\/a> <strong>Colquhoun, D. (1987)<\/strong>. Affinity, efficacy and receptor classification: is the classical theory still useful? In <em>Perspectives on hormone receptor classification<\/em>, ed. Black, J. W., pp. 103-114. Alan R. Liss Inc., New York. [<a href=\"colquhoun-1987.pdf\" target=\"_blank\" rel=\"noopener noreferrer\">get pdf file<\/a>]<br \/><i><span style=\"color: #800000;\">This paper explains why Stephenson&#8217;s quantitative formulation contained an error, and how this error implied that none of the published methods for experimental determination of &#8216;affinity&#8217; and &#8216;efficacy&#8217; could actually achieve the separation of these quantities that had been claimed for them.<\/span> <\/i>\u00a0\u00a0\u00a0[#dc87]<\/p>\n<p><!-- \/wp:paragraph --><\/p>","protected":false},"excerpt":{"rendered":"<p>Jump to follow-up Some of our main papers since 2003 are listed below, with commentaries and reprints. Some older papers and classics can be&nbsp;downloaded here too. .For more papers, follow these links. Lucia Sivilotti\u2018s papers are listed also on her&nbsp;UCL &hellip; <a href=\"https:\/\/onemol.org.uk\/?page_id=10\">Continue reading <span class=\"meta-nav\">&rarr;<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"open","ping_status":"open","template":"","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"jetpack_post_was_ever_published":false,"footnotes":""},"class_list":["post-10","page","type-page","status-publish","hentry"],"jetpack_shortlink":"https:\/\/wp.me\/P3xlLM-a","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/onemol.org.uk\/index.php?rest_route=\/wp\/v2\/pages\/10","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/onemol.org.uk\/index.php?rest_route=\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/onemol.org.uk\/index.php?rest_route=\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/onemol.org.uk\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/onemol.org.uk\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=10"}],"version-history":[{"count":153,"href":"https:\/\/onemol.org.uk\/index.php?rest_route=\/wp\/v2\/pages\/10\/revisions"}],"predecessor-version":[{"id":761,"href":"https:\/\/onemol.org.uk\/index.php?rest_route=\/wp\/v2\/pages\/10\/revisions\/761"}],"wp:attachment":[{"href":"https:\/\/onemol.org.uk\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=10"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}