An Epilepsy-Related Region in the GABA_A Receptor Mediates Long-Distance Effects on GABA and Benzodiazepine Binding Sites

Authors

Marcel P. Goldschen-Ohm, University of Wisconsin - Madison
David A. Wagner, Marquette UniversityFollow
Steven Petrou, University of Melbourne
Mathew V. Jones, University of Melbourne

Document Type

Article

Language

eng

Format of Original

11 p.

Publication Date

1-2010

Publisher

American Society for Pharmacology and Experimental Therapeutics

Source Publication

Molecular Pharmacology

Source ISSN

0026-895X

Abstract

The GABA_A receptor mutation γ₂R43Q causes absence epilepsy in humans. Homology modeling suggests that γ₂Arg43, γ₂Glu178, and β₂Arg117 participate in a salt-bridge network linking the γ₂ and β₂ subunits. Here we show that several mutations at these locations exert similar long-distance effects on other intersubunit interfaces involved in GABA and benzodiazepine binding. These mutations alter GABA-evoked receptor kinetics by slowing deactivation, enhancing desensitization, or both. Kinetic modeling and nonstationary noise analysis for γ₂R43Q reveal that these effects are due to slowed GABA unbinding and slowed recovery from desensitization. Both γ₂R43Q and β₂R117K also speed diazepam dissociation from the receptor’s benzodiazepine binding interface, as assayed by the rate of decay of diazepam-induced potentiation of GABA-evoked currents. These data demonstrate that γ₂Arg43 and β₂Arg117 similarly regulate the stability of both the GABA and benzodiazepine binding sites at the distant β/α and α/γ intersubunit interfaces, respectively. A simple explanation for these results is that γ₂Arg43 and β₂Arg117 participate in interactions between the γ₂ and β₂ subunits, disruptions of which alter the neighboring intersubunit binding sites in a similar fashion. In addition, γ₂Arg43 and γ₂Glu178 regulate desensitization, probably mediated within the transmembrane domains near the pore. Therefore, mutations at the γ/β intersubunit interface have specific long-distance effects that are propagated widely throughout the GABA_A receptor protein.

Comments

Molecular Pharmacology, Vol. 77, No. 1 (January 2010): 35-45. DOI.

Recommended Citation

Goldschen-Ohm, Marcel P.; Wagner, David A.; Petrou, Steven; and Jones, Mathew V., "An Epilepsy-Related Region in the GABA_A Receptor Mediates Long-Distance Effects on GABA and Benzodiazepine Binding Sites" (2010). Biological Sciences Faculty Research and Publications. 309.
https://epublications.marquette.edu/bio_fac/309