Additional file 1 of Cooperative binding mitigates the high-dose hook effect

Supplemental text. (PDF 106 kb

Additional file 2 of Cooperative binding mitigates the high-dose hook effect

Matlab code used to produce Figs. 4 and 6. (M 1.28 kb

Effects of full and partial agonists.

<p>(<b>A</b>) shows the small, medium and large conductance states upon stimulation with glutamate where the large state is stabilized (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116616#pone.0116616.s002" target="_blank">S1 Supporting model</a>). The relative frequency of the small conductance state (green line) is 0.6 at a ligand concentration of 1 μM and decreases when the ligand concentration is increased, whereas the medium conductance state (blue line) reaches its peak at a concentration above 0.1 μM and most receptors are found in the large conductance state (black line) at 10 μM. The dots represent experimental data [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116616#pone.0116616.ref015" target="_blank">15</a>]. (<b>B</b>) stabilization of GluA3/GluK2 receptor large conductance state upon stimulation with quisqualate [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116616#pone.0116616.ref002" target="_blank">2</a>] (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116616#pone.0116616.s003" target="_blank">S2 Supporting model</a>). The relative frequencies of the basal state (red line) and small state (green line) of the receptor are 0.7 and 0.25 at 1 μM and decrease when ligand concentration is increased, whereas the medium (blue) and large (black) conductance states increase and reach 0.1 and 0.9 respectively at 1 mM. The line in magenta shows the saturation function. (<b>C</b>) stabilization of GluR2 homomeric receptors intermediate conductance state upon stimulation with large willardiines (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116616#pone.0116616.s004" target="_blank">S3 Supporting model</a>). The relative frequencies of the small state (green lines) is decreased and the medium (blue) and large (black) states are increased when the ligand concentration increases at stimulation with both BrW and IW. At a ligand concentration of 10 mM the relative frequency of the medium state was 0.65 and 0.35 at stimulation with IW (dashed) and BrW (solid) respectively [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116616#pone.0116616.ref010" target="_blank">10</a>].</p

Dissociation constants for partial agonists.

<p>Dissociation constants for partial agonists.</p

State transitions of a single channel.

<p>A single channel progresses from a non-liganded basal state to a fully liganded large open state within 0.4 ms upon stimulation with 1 μM full agonist (the original STOIC model is provided as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116616#pone.0116616.s005" target="_blank">S4 Supporting model</a>). It should be noted that the simulation is stochastic and this is one of the possible paths the receptor takes to its stable state.</p

Allosteric and dissociation constants determined for full agonists.

<p>Allosteric and dissociation constants determined for full agonists.</p

Kinetic behaviour of synaptic AMPARs.

<p>(<b>A</b>) The blue trace shows the average synaptic current, which reaches its peak within fractions of ms (n = 7). The black bar represents the depolarisation of the pre-synapic terminal. (<b>B</b>) Kinetics of the subconductance states of an AMPA receptor population (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116616#pone.0116616.s005" target="_blank">S4 Supporting model</a>). Left plot, deterministic simulation of a population of GluA3/GluK2 receptors by 1 μM of agonist. Right plot, stochastic simulation of a population of 50 receptors. Only the most populated states are represented for sake of clarity.</p