Analysis of the Function of Receptor Oligomers by Operational Models of Agonism

Allosteric binding cooperativity in a kinetic context

“…Furthermore, a combination of the two ligands would synergistically favor the desired effect. 13 This behavior was modeled in 14 by using a heterodimer model under equilibrium conditions. 10 To do so, proper values for the parameters describing receptor function under equilibrium conditions were chosen; in particular, values either greater than one or lower than one for the functional cooperativities in their respective Gi or Gq signaling pathways were chosen.…”

“…10 To do so, proper values for the parameters describing receptor function under equilibrium conditions were chosen; in particular, values either greater than one or lower than one for the functional cooperativities in their respective Gi or Gq signaling pathways were chosen. 14 A second layer of complexity comes from considering the mutual influence between the receptors through ligand binding. Thus, if we are including a combination of two ligands, that is, a strong agonist A for mGlu2 and an inverse agonist B for 5HT2A, a binding cooperativity a > 1 would favor the binding of the two ligands.…”

“…As a result, there is an increase in the potency and efficacy of the system with a displacement of the black curve both left and upwards (the maximum response is increased). Note: mathematical expressions of the maximum response (the limiting value of E/E m as [A] or [B] increase) can be found in 14 . FEATURE ter correlation to its intrinsic efficacy.…”