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Correspondence  |   February 2017
Flumazenil Modulation of the γ-Aminobutyric Acid Type A Receptor: Competitive versus Noncompetitive Antagonism at the Agonist-binding Site
Author Notes
  • Massachusetts General Hospital, Boston, Massachusetts. draines@partners.org
  • (Accepted for publication October 11, 2016.)
    (Accepted for publication October 11, 2016.)×
Article Information
Correspondence
Correspondence   |   February 2017
Flumazenil Modulation of the γ-Aminobutyric Acid Type A Receptor: Competitive versus Noncompetitive Antagonism at the Agonist-binding Site
Anesthesiology 2 2017, Vol.126, 350-351. doi:10.1097/ALN.0000000000001444
Anesthesiology 2 2017, Vol.126, 350-351. doi:10.1097/ALN.0000000000001444
To the Editor:
A variety of therapeutic drugs administered by anesthesiologists are commonly and effectively pharmacologically reversed. Unfortunately, and somewhat ironically, general anesthetics are not among them. It was, therefore, with great interest that I read the article “Effects of γ-Aminobutyric Acid Type A Receptor Modulation by Flumazenil on Emergence from General Anesthesia.1  Among the many interesting findings, this study demonstrated that flumazenil can reduce isoflurane-mediated potentiation of the γ-aminobutyric acid (GABA) type A receptor (GABAAR) in the presence of GABA, weakly activate GABAARs in the absence of GABA, and shorten the time required for the electroencephalogram to return to an awake-like state after isoflurane administration.
Based on flumazenil’s ability to reduce maximal peak currents evoked by GABA without shifting the GABA concentration–response relationship (fig. 71 ), the authors concluded that the drug binds to the GABA-binding site, where it acts as a competitive antagonist. However, I wish to point out that such behavior is not indicative of a competitive antagonist. Rather, it is the hallmark of a noncompetitive antagonist. Had flumazenil acted as a competitive antagonist of GABA, the expected result would have been quite different: to shift the GABA concentration–response relationship rightward toward higher concentrations without reducing the peak currents evoked by maximal GABA concentrations. More broadly, I believe that this fact calls into question the authors’ mechanistic conclusion that the various actions of flumazenil revealed by their in vitro studies and the variable results of clinical studies reported by other groups can be explained by flumazenil’s interactions with the GABA-binding site.
There are multiple binding sites for benzodiazepines and benzodiazepine-like drugs on the GABAAR that are known to positively and/or negatively allosterically modulate receptor function. There is the classical high-affinity benzodiazepine site located in the extracellular domain at the α+–γ- subunit interface, which is distinct from the GABA-binding site located in the extracellular domain at the β+–α- subunit interface.2,3  There are also low-affinity sites located in the extracellular domain at the α+–β- subunit interface and at subunit interfaces in the transmembrane domain where several classes of general anesthetics bind.4–6  As flumazenil is a benzodiazepine analog that the authors’ data show acts noncompetitively with GABA on the GABAAR, it seems more likely that flumazenil produces its inhibitory and enhancing receptor actions by binding to the multitude of sites that are known to bind benzodiazepines and benzodiazepine-like drugs rather than by directly binding to the agonist (i.e., GABA)–binding site.
Competing Interests
The author declares no competing interests.
Douglas E. Raines, M.D., Massachusetts General Hospital, Boston, Massachusetts. draines@partners.org
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