TY - JOUR
T1 - High constitutive activity accounts for the combination of enhanced direct activation and reduced potentiation in mutated GABAA receptors
AU - Germann, Allison L.
AU - Shin, Daniel J.
AU - Kuhrau, Christina R.
AU - Johnson, Alexander D.
AU - Evers, Alex S.
AU - Akk, Gustav
N1 - Funding Information:
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM108580 and R01-GM108799], the Center for the Investigation of Membrane Excitability Diseases at Washington University [Grant CIMED-17-03], and the Taylor Family Institute for Innovative Psychiatric Research. https://doi.org/10.1124/mol.117.111435.
Funding Information:
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM108580 and R01-GM108799], the Center for the Investigation of Membrane Excitability Diseases at Washington University [Grant CIMED-17-03], and the Taylor Family Institute for Innovative Psychiatric Research.
Publisher Copyright:
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2018/5
Y1 - 2018/5
N2 - GABAA receptors activated by the transmitter GABA are potentiated by several allosterically acting drugs, including the intravenous anesthetic propofol. Propofol can also directly activate the receptor, albeit at higher concentrations. Previous functional studies have identified amino acid residues whose substitution reduces potentiation of GABA-activated receptors by propofol while enhancing the ability of propofol to directly activate the receptor. One interpretation of such observations is that the mutation has specific effects on the sites or processes involved in potentiation or activation. We show here that divergent effects on potentiation and direct activation can be mediated by increased constitutive open probability in the mutant receptor without any specific effect on the interactions between the allosteric drug and the receptor. By simulating GABAA receptor activity using the concerted transition model, we demonstrate that the predicted degree of potentiation is reduced as the level of constitutive activity increases. The model further predicts that a potentiating effect of an allosteric modulator is a computable value that depends on the level of constitutive activity, the amplitude of the response to the agonist, and the amplitude of the direct activating response to the modulator. Specific predictions were confirmed by electrophysiological data from the binary a1b3 and concatemeric ternary b2a1g2L1b2a1 GABAA receptors. The corollaries of reduced potentiation due to increased constitutive activity are isobolograms that conform to simple additivity and a loss of separation between the concentration-response relationships for direct activation and potentiation.
AB - GABAA receptors activated by the transmitter GABA are potentiated by several allosterically acting drugs, including the intravenous anesthetic propofol. Propofol can also directly activate the receptor, albeit at higher concentrations. Previous functional studies have identified amino acid residues whose substitution reduces potentiation of GABA-activated receptors by propofol while enhancing the ability of propofol to directly activate the receptor. One interpretation of such observations is that the mutation has specific effects on the sites or processes involved in potentiation or activation. We show here that divergent effects on potentiation and direct activation can be mediated by increased constitutive open probability in the mutant receptor without any specific effect on the interactions between the allosteric drug and the receptor. By simulating GABAA receptor activity using the concerted transition model, we demonstrate that the predicted degree of potentiation is reduced as the level of constitutive activity increases. The model further predicts that a potentiating effect of an allosteric modulator is a computable value that depends on the level of constitutive activity, the amplitude of the response to the agonist, and the amplitude of the direct activating response to the modulator. Specific predictions were confirmed by electrophysiological data from the binary a1b3 and concatemeric ternary b2a1g2L1b2a1 GABAA receptors. The corollaries of reduced potentiation due to increased constitutive activity are isobolograms that conform to simple additivity and a loss of separation between the concentration-response relationships for direct activation and potentiation.
UR - http://www.scopus.com/inward/record.url?scp=85045010648&partnerID=8YFLogxK
U2 - 10.1124/mol.117.111435
DO - 10.1124/mol.117.111435
M3 - Article
C2 - 29439087
AN - SCOPUS:85045010648
VL - 93
SP - 468
EP - 476
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 5
ER -