NDLI: Enhancement of 5-containing Î³-aminobutyric acid type A receptors by the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6) is abolished by the ß3(N265M) mutation.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Burkat, Paul M. Lor, Chong Perouansky, Misha Pearce, Robert A.
Description	Author Affiliation: Burkat PM ( From the Department of Anesthesiology, University of Wisconsin SMPH, Madison, Wisconsin.)
Abstract	BACKGROUND: Modulation of Î³-aminobutyric acid type A receptors (GABAARs) by general anesthetics may contribute to their ability to produce amnesia. Receptors containing 5 subunits, which mediate tonic and slow synaptic inhibition, are co-localized with ß3 and Î³2 subunits in dendritic layers of the hippocampus and are sensitive to low (amnestic) concentrations of anesthetics. Because 5 and ß3 subunits influence performance in hippocampus-dependent learning tasks in the presence and absence of general anesthetics, and the experimental inhaled drug 1,2-dichlorohexafluorocyclobutane (F6) impairs hippocampus-dependent learning, we hypothesized that F6 would modulate receptors that incorporate 5 and ß3 subunits. We hypothesized further that the ß3(N265M) mutation, which controls receptor modulation by general anesthetics, would similarly influence modulation by F6. METHODS: Using whole-cell electrophysiologic recording techniques, we tested the effects of F6 at concentrations ranging from 4 to 16 µM on receptors expressed in human embryonic kidney 293 cells. We measured drug modulation of wild-type 5ß3 and 5ß3Î³2L GABAARs and receptors harboring the ß3(N265M) mutation. We also tested the effects of F6 on 1ß2Î³2L receptors, which were reported previously to be insensitive to this drug when expressed in Xenopus oocytes. RESULTS: F6 enhanced the responses of wild-type 5ß3Î³2L but not 1ß2Î³2L receptors to low concentrations of GABA in a concentration-dependent manner. Receptors that incorporated the mutant ß3(N265M) subunit were insensitive to F6. When applied together with a high concentration of GABA, F6 blocked currents through 5ß3 but not 5ß3Î³2L receptors. F6 did not alter deactivation of 5ß3Î³2L receptors after brief high- concentration pulses of GABA. CONCLUSIONS: The nonimmobilizer F6 modulates GABAARs in a manner that depends on subunit composition and mode of receptor activation by GABA, supporting a possible role for 5-containing receptors in suppression of learning and memory by F6. Furthermore, common structural requirements indicate that similar molecular mechanisms may be responsible for the enhancing effects of F6 and conventional general anesthetics.
File Format	HTM / HTML
ISSN	00032999
e-ISSN	15267598
DOI	10.1213/ANE.0000000000000423
Journal	Anesthesia & Analgesia
Issue Number	6
Volume Number	119
Language	English
Publisher	Lippincott Williams & Wilkins
Publisher Date	2014-12-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Anesthesiology Anesthetics Pharmacology Chlorofluorocarbons Cyclobutanes Gaba Modulators Mutation Receptors, Gaba-a Drug Effects Genetics Gamma-aminobutyric Acid Dose-response Relationship, Drug Hek293 Cells Kinetics Membrane Potentials Metabolism Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Anesthesiology and Pain Medicine

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Enhancement of α5-Containing Gamma-Aminobutyric Acid TypeAReceptors by the Nonimmobilizer 1,2-Dichlorohexafluorocyclobutane (F6) is Abolished by the β3(N265M) Mutation

Anesthetics discriminate between tonic and phasic gamma-aminobutyric acid receptors on hippocampal CA1 neurons.

Isoflurane Potentiation of $GABA_{A}$ Receptors Is Reduced but Not Eliminated by the β3(N265M) Mutation

The anesthetic-like effects of diverse compounds on wild-type and mutant gamma-aminobutyric acid type A and glycine receptors.

Amino Acid Volume and Hydropathy of a Transmembrane Site Determine Glycine and Anesthetic Sensitivity of Glycine Receptors

Stoichiometry of δ subunit containing $GABA_{A}$ receptors

Comparison of anaesthetic and non-anaesthetic effects on depolarization-evoked glutamate and GABA release from mouse cerebrocortical slices.

Agonist-dependent endocytosis of Î³-aminobutyric acid type A (GABAA) receptors revealed by a Î³2(R43Q) epilepsy mutation.

Isovaleric, methylmalonic, and propionic acid decrease anesthetic EC50 in tadpoles, modulate glycine receptor function, and interact with the lipid 1,2-dipalmitoyl-Sn-glycero-3-phosphocholine.

Enhancement of 5-containing Î³-aminobutyric acid type A receptors by the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6) is abolished by the ß3(N265M) mutation.

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Enhancement of α5-Containing Gamma-Aminobutyric Acid TypeAReceptors by the Nonimmobilizer 1,2-Dichlorohexafluorocyclobutane (F6) is Abolished by the β3(N265M) Mutation

Anesthetics discriminate between tonic and phasic gamma-aminobutyric acid receptors on hippocampal CA1 neurons.

Isoflurane Potentiation of $GABA_{A}$ Receptors Is Reduced but Not Eliminated by the β3(N265M) Mutation

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Stoichiometry of δ subunit containing $GABA_{A}$ receptors

Comparison of anaesthetic and non-anaesthetic effects on depolarization-evoked glutamate and GABA release from mouse cerebrocortical slices.

Agonist-dependent endocytosis of Î³-aminobutyric acid type A (GABAA) receptors revealed by a Î³2(R43Q) epilepsy mutation.

Isovaleric, methylmalonic, and propionic acid decrease anesthetic EC50 in tadpoles, modulate glycine receptor function, and interact with the lipid 1,2-dipalmitoyl-Sn-glycero-3-phosphocholine.

Enhancement of 5-containing Î³-aminobutyric acid type A receptors by the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6) is abolished by the ß3(N265M) mutation.