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Allosteric Co-Agonist Model for Etomidate

Monod-Wyman-Changeux (MWC) allosterism is a simple concept that was first formalized in 1965. Nonetheless, it is unfamiliar to many who study ligand-gated ion channels, where simple linear models have dominated.

The simplest type of MWC model has only two functional states: Inactive and Active, which for ion channels can be thought of as closed and open. MWC explicitly allows transitions between these functional states in the absence of any modulating ligands such as GABA (Figure 1). This is consistent with thermodynamic principles, because infinitely high energy barriers do not exist. There is also evidence that many ion channels do in fact spontaneously open in the absence of agonists and mutations can increase the probability of spontaneous activation. The equilibrium between these two states is described by a single parameter, L0 = [R]/[O].

Figure 1

Agonism in MWC allosteric models is simply due to ligands binding preferentially to the open state (Figure 2). Thus an agonist stabilizes the open state relative to the resting (closed) state. This is formalized by adding two additional equilibrium parameters, the dissociation constant for agonist binding to the closed receptor (KG) and the dissociation constant for agonist binding to the open receptor (K*G). The efficacy of agonist G is simply described by the ratio K*G/KG, which we define as c. The equilibrium system now has 4 states and is described by 3 equilibrium parameters. Note that the cyclic constraints force the equilibrium between closed agonist bound states and open agonist bound states to be cL0. When c is less than 1.0, G is an agonist, because the ratio of open to closed states will increase. These models also allow for the concept of inverse agonism, which is when c > 1.0. In this case, the closed-inactive state is stabilized relative to the open-active state.

Figure 2

MWC co-agonism is another simple modification of this model, created by adding another set of sites where another ligand (etomidate) can bind. Etomidate is an allosteric agonist, because it, like GABA, shifts the open-closed equilibrium toward the open state when bound (it has lower efficacy than GABA). To quantify this second agonist action, we need to add 2 additional equilibrium binding parameters, K*E and KE, which have a ratio d (d<1), the etomidate efficacy. This model has 6 states and 5 parameters.

Figure 3

To be a fully allosteric model, the receptor must also allow both GABA and etomidate to bind at the same time, creating another set of states. Note that the number of equilibrium parameters for the 8-state model remains 5. The states with both GABA and etomidate have the highest probability of opening with a closed-open equilibrium of L0cd.

Figure 4

Of course, GABAA receptors have two GABA sites, which we have treated as identical (i.e. identical GABA binding affinities in the closed and open states). Our data on etomidate modulation was fit best by a model which also had two identical etomidate sites (models with up to 5 identical sites were assessed). By keeping the sites identical, we therefore maintained only 5 equilibrium parameters, despite increase the number of states to 18.

Figure 5

 

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