A Single Phenylalanine Residue in the Main Intracellular Loop of α1 γ-Aminobutyric Acid Type A and Glycine Receptors Influences Their Sensitivity to Propofol

Authors

Gustavo Moraga-Cid, University of ConcepcionFollow
Gonzalo E. Yevenes, University of ConcepcionFollow
Günther Schmalzing, Rheinisch-Westfaelische Technische Hochschule
Robert W. Peoples, Marquette UniversityFollow
Luis G. Aguayo, University of ConcepcionFollow

Document Type

Article

Language

eng

Format of Original

10 p.

Publication Date

9-2011

Publisher

Lippincott Williams & Wilkins, Inc.

Source Publication

Anesthesiology

Source ISSN

0003-3022

Original Item ID

doi: 10.1097/ALN.0b013e31822550f7

Abstract

Background: The intravenous anesthetic propofol acts as a positive allosteric modulator of glycine (GlyRs) and γ-aminobutyric acid type A (GABA_ARs) receptors. Although the role of transmembrane residues is recognized, little is known about the involvement of other regions in the modulatory effects of propofol. Therefore, the influence of the large intracellular loop in propofol sensitivity of both receptors was explored. Methods: The large intracellular loop of α₁ GlyRs and α₁β₂ GABA_ARs was screened using alanine replacement. Sensitivity to propofol was studied using patch-clamp recording in HEK293 cells transiently transfected with wild type or mutant receptors. Results: Alanine mutation of a conserved phenylalanine residue within the α₁ large intracellular loop significantly reduced propofol enhancement in both GlyRs (360 ± 30 vs. 75 ± 10%, mean ± SEM) and GABA_ARs (361 ± 49% vs. 80 ± 23%). Remarkably, propofol-hyposensitive mutant receptors retained their sensitivity to other allosteric modulators such as alcohols, etomidate, trichloroethanol, and isoflurane. At the single-channel level, the ability of propofol to increase open probability was significantly reduced in both α₁ GlyR (189 ± 36 vs. 22 ± 13%) and α₁β₂ GABA_AR (279 ± 29 vs. 29 ± 11%) mutant receptors. Conclusion: In this study, it is demonstrated that the large intracellular loop of both GlyR and GABA_AR has a conserved single phenylalanine residue (F380 and F385, respectively) that influences its sensitivity to propofol. Results suggest a new role of the large intracellular loop in the allosteric modulation of two members of the Cys-loop superfamily. Thus, these data provide new insights into the molecular framework behind the modulation of inhibitory ion channels by propofol.

Comments

Accepted version. Anesthesiology, Vol. 115, No. 3 (September, 2011): 464–473. DOI. © 2011 American Society of Anesthesiologists, Inc. Used with permission.

Recommended Citation

Moraga-Cid, Gustavo; Yevenes, Gonzalo E.; Schmalzing, Günther; Peoples, Robert W.; and Aguayo, Luis G., "A Single Phenylalanine Residue in the Main Intracellular Loop of α1 γ-Aminobutyric Acid Type A and Glycine Receptors Influences Their Sensitivity to Propofol" (2011). Biomedical Sciences Faculty Research and Publications. 2.
https://epublications.marquette.edu/biomedsci_fac/2