Analysis of GABAA Receptor Activation by Combinations of Agonists Acting at the Same or Distinct Binding Sites.

Under both physiologic and clinical conditions GABAA receptors are exposed to multiple agonists, including the transmitter GABA, endogenous or exogenous neuroactive steroids, and various GABAergic anesthetic and sedative drugs. The functional output of the receptor reflects the interplay among all active agents. We have investigated the activation of the concatemeric α1β2γ2L GABAA receptor by combinations of agonists. Simulations of receptor activity using the coagonist concerted transition model demonstrate that the response amplitude in the presence of agonist combinations is highly dependent on whether the paired agonists interact with the same or distinct sites. The experimental data for receptor activation by agonist combinations were in agreement with the established views of the overlap of binding sites for several pairs of orthosteric (GABA, β-alanine, and piperidine-4-sulfonic acid) and/or allosteric agents (propofol, pentobarbital, and several neuroactive steroids). Conversely, the degree of potentiation when two GABAergic agents are coapplied can be used to determine whether the compounds act by binding to the same or distinct sites. We show that common interaction sites mediate the actions of 5α- and 5β-reduced neuroactive steroids, and natural and enantiomeric steroids. Furthermore, the results indicate that the anesthetics propofol and pentobarbital interact with partially shared binding sites. We propose that the findings may be used to predict the efficacy of drug mixtures in combination therapy and thus have potential clinical relevance.