How Understanding Weber's Law Led to an Understanding of the Receptor Response

An understanding of Weber's law in terms of the net shift of weights on a simple balance (see: Weber's Law Modeled by the Mathematical Description of a Beam Balance) led to a better measure for the receptor response.

By combining Langmuir binding to two receptor states representing high and low affinity states analogous to the two pans at the end of the arms of a simple balance, an expression can be derived that describes ligand binding and activation of receptors remarkably well (see: The Biophysical Basis for the Graphical Representations and Method for determining drug compositions to prevent desensitization of cellular receptors). It should be noted that these two states were previously given a biophysical representation (see: Activation of G Protein-Coupled Receptors Entails Cysteine Modulation of Agonist Binding and Molecular dynamics of a biophysical model for β 2-adrenergic and G protein-coupled receptor activation).

Whether or not these biophysical descriptions are accurate or not is somewhat immaterial to the basic understanding regarding the biophysical basis for these two possible states. I would argue that these descriptions satisfy a large number of essential criteria that are largely missed or glossed over in many attempts to model the possible transitions from inactive to active receptor states. Without going into too much detail, I will just mention that the free energy change between these states is quit low (estimated to be 2-3 kcal/mol), which suggests that an electrostatic change may be a better candidate for the initial change to produce receptor activation. This better accounts for the oxidation-reduction properties and pH-dependence of many of the G protein-coupled receptors. So if the exact details of the above models aren't perfect, I still think that they're on the right tract.

Over the years, this approach has been able to provide biophysical descriptions for ligand efficacy, affinity, spare receptors, tachyphylaxis and rapid desensitization; as well as the effects of receptor overexpression and agonist/antagonist combinations on the receptor response (see: Method for determining drug-molecular combinations that modulate and enhance the therapeutic safety and efficacy of biological or pharmaceutical drugs).

After almost thirty years of development, perhaps it is time to attempt the transition to a cleaner biophysical definition for the receptor response. I certainly realize that this is a quixotic quest, but I believe that it will ultimately be worth the effort!