Title:Perspective on the Relationship between GABAA Receptor Activity and the
Apparent Potency of an Inhibitor
Volume: 20
Issue: 1
Author(s): Allison L. Germann, Spencer R. Pierce, Alex S. Evers, Joe Henry Steinbach and Gustav Akk*
Affiliation:
- Department of Anesthesiology (ALG, SRP, ASE, JHS, GA), Washington University School of Medicine, St. Louis, MO 63110,United States
- The Taylor Family
Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO 63110, USA
Keywords:
GABAA receptor, activation, inhibition, modeling, IC50.
Abstract: Background: In electrophysiological experiments, inhibition of a receptor-channel, such
as the GABAA receptor, is measured by co-applying an agonist producing a predefined control response
with an inhibitor to calculate the fraction of the control response remaining in the presence
of the inhibitor. The properties of the inhibitor are determined by fitting the inhibition concentration-
response relationship to the Hill equation to estimate the midpoint (IC50) of the inhibition curve
Objective: We sought to estimate sensitivity of the fitted IC50 to the level of activity of the control
response
Methods: The inhibition concentration-response relationships were calculated for models with distinct
mechanisms of inhibition. In Model I, the inhibitor acts allosterically to stabilize the resting
state of the receptor. In Model II, the inhibitor competes with the agonist for a shared binding site.
In Model III, the inhibitor stabilizes the desensitized state.
Results: The simulations indicate that the fitted IC50 of the inhibition curve is sensitive to the degree
of activity of the control response. In Models I and II, the IC50 of inhibition was increased as the
probability of being in the active state (PA) of the control response increased. In Model III, the IC50
of inhibition was reduced at higher PA.
Conclusion: We infer that the apparent potency of an inhibitor depends on the PA of the control response.
While the calculations were carried out using the activation and inhibition properties that are
representative of the GABAA receptor, the principles and conclusions apply to a wide variety of receptor-
channels.
