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Monod-Wyman-Changeux Allosteric Shift Analysis in Mutant α1β3γ2L GABAA Receptors Indicates Selectivity and Crosstalk among Intersubunit Transmembrane Anesthetic Sites.
Szabo A
,
Nourmahnad A
,
Halpin E
,
Forman SA
.
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Propofol, etomidate, and barbiturate anesthetics are allosteric coagonists at pentameric α1β3γ2 GABAA receptors, modulating channel activation via four biochemically established intersubunit transmembrane pockets. Etomidate selectively occupies the two β +/α - pockets, the barbiturate photolabel R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid (R-mTFD-MPAB) occupies homologous α +/β - and γ +/β - pockets, and propofol occupies all four. Functional studies of mutations at M2-15' or M3-36' loci abutting these pockets provide conflicting results regarding their relative contributions to propofol modulation. We electrophysiologically measured GABA-dependent channel activation in α1β3γ2L or receptors with single M2-15' (α1S270I, β3N265M, and γ2S280W) or M3-36' (α1A291W, β3M286W, and γ2S301W) mutations, in the absence and presence of equipotent clinical range concentrations of etomidate, R-mTFD-MPAB, and propofol. Estimated open probabilities were calculated and analyzed using global two-state Monod-Wyman-Changeux models to derive log(d) parameters proportional to anesthetic-induced channel modulating energies (where d is the allosteric anesthetic shift factor). All mutations reduced the log(d) values for anesthetics occupying both abutting and nonabutting pockets. The Δlog(d) values [log(d, mutant) - log(d, wild type)] for M2-15' mutations abutting an anesthetic's biochemically established binding sites were consistently larger than the Δlog(d) values for nonabutting mutations, although this was not true for the M3-36' mutant Δlog(d) values. The sums of the anesthetic-associated Δlog(d) values for sets of M2-15' or M3-36' mutations were all much larger than the wild-type log(d) values. Mutant Δlog(d) values qualitatively reflect anesthetic site occupancy patterns. However, the lack of Δlog(d) additivity undermines quantitative comparisons of distinct site contributions to anesthetic modulation because the mutations impaired both abutting anesthetic binding effects and positive cooperativity between anesthetic binding sites.
Baumann,
Subunit arrangement of gamma-aminobutyric acid type A receptors.
2001, Pubmed,
Xenbase
Baumann,
Subunit arrangement of gamma-aminobutyric acid type A receptors.
2001,
Pubmed
,
Xenbase
Belelli,
The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid.
1997,
Pubmed
,
Xenbase
Brohan,
The Role of GABA Receptor Agonists in Anesthesia and Sedation.
2017,
Pubmed
Cao,
Enhanced GABAergic actions resulting from the coapplication of the steroid 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) with propofol or diazepam.
2018,
Pubmed
,
Xenbase
Chang,
Allosteric activation mechanism of the alpha 1 beta 2 gamma 2 gamma-aminobutyric acid type A receptor revealed by mutation of the conserved M2 leucine.
1999,
Pubmed
,
Xenbase
Chiara,
Specificity of intersubunit general anesthetic-binding sites in the transmembrane domain of the human α1β3γ2 γ-aminobutyric acid type A (GABAA) receptor.
2013,
Pubmed
Desai,
Gamma-amino butyric acid type A receptor mutations at beta2N265 alter etomidate efficacy while preserving basal and agonist-dependent activity.
2009,
Pubmed
,
Xenbase
Feng,
Etomidate produces similar allosteric modulation in α1β3δ and α1β3γ2L GABA(A) receptors.
2014,
Pubmed
,
Xenbase
Forman,
Mapping General Anesthetic Sites in Heteromeric γ-Aminobutyric Acid Type A Receptors Reveals a Potential For Targeting Receptor Subtypes.
2016,
Pubmed
Forman,
Mutations in the GABAA receptor that mimic the allosteric ligand etomidate.
2012,
Pubmed
,
Xenbase
Forman,
Monod-Wyman-Changeux allosteric mechanisms of action and the pharmacology of etomidate.
2012,
Pubmed
Forman,
Combining Mutations and Electrophysiology to Map Anesthetic Sites on Ligand-Gated Ion Channels.
2018,
Pubmed
,
Xenbase
Germann,
High Constitutive Activity Accounts for the Combination of Enhanced Direct Activation and Reduced Potentiation in Mutated GABAA Receptors.
2018,
Pubmed
,
Xenbase
Guitchounts,
Two etomidate sites in α1β2γ2 γ-aminobutyric acid type A receptors contribute equally and noncooperatively to modulation of channel gating.
2012,
Pubmed
,
Xenbase
Jayakar,
Multiple propofol-binding sites in a γ-aminobutyric acid type A receptor (GABAAR) identified using a photoreactive propofol analog.
2014,
Pubmed
Jayakar,
Positive and Negative Allosteric Modulation of an α1β3γ2 γ-Aminobutyric Acid Type A (GABAA) Receptor by Binding to a Site in the Transmembrane Domain at the γ+-β- Interface.
2015,
Pubmed
Krasowski,
Propofol and other intravenous anesthetics have sites of action on the gamma-aminobutyric acid type A receptor distinct from that for isoflurane.
1998,
Pubmed
Li,
The neurosteroid 5β-pregnan-3α-ol-20-one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2L GABAA receptors.
2014,
Pubmed
,
Xenbase
Li,
Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog.
2006,
Pubmed
Li,
The benzodiazepine diazepam potentiates responses of α1β2γ2L γ-aminobutyric acid type A receptors activated by either γ-aminobutyric acid or allosteric agonists.
2013,
Pubmed
Maldifassi,
Functional sites involved in modulation of the GABAA receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital.
2016,
Pubmed
,
Xenbase
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Nourmahnad,
Tryptophan and Cysteine Mutations in M1 Helices of α1β3γ2L γ-Aminobutyric Acid Type A Receptors Indicate Distinct Intersubunit Sites for Four Intravenous Anesthetics and One Orphan Site.
2016,
Pubmed
,
Xenbase
Olsen,
GABA A receptors: subtypes provide diversity of function and pharmacology.
2009,
Pubmed
Phulera,
Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA.
2018,
Pubmed
Ruesch,
An allosteric coagonist model for propofol effects on α1β2γ2L γ-aminobutyric acid type A receptors.
2012,
Pubmed
,
Xenbase
Rüsch,
Gating allosterism at a single class of etomidate sites on alpha1beta2gamma2L GABA A receptors accounts for both direct activation and agonist modulation.
2004,
Pubmed
,
Xenbase
Scheller,
Coupled and uncoupled gating and desensitization effects by pore domain mutations in GABA(A) receptors.
2002,
Pubmed
Shin,
The Actions of Drug Combinations on the GABAA Receptor Manifest as Curvilinear Isoboles of Additivity.
2017,
Pubmed
,
Xenbase
Shin,
Analysis of GABAA Receptor Activation by Combinations of Agonists Acting at the Same or Distinct Binding Sites.
2019,
Pubmed
,
Xenbase
Shin,
Propofol Is an Allosteric Agonist with Multiple Binding Sites on Concatemeric Ternary GABAA Receptors.
2018,
Pubmed
,
Xenbase
Siegwart,
Mutational analysis of molecular requirements for the actions of general anaesthetics at the gamma-aminobutyric acidA receptor subtype, alpha1beta2gamma2.
2003,
Pubmed
Sigel,
Structure, function, and modulation of GABA(A) receptors.
2012,
Pubmed
Steinbach,
Applying the Monod-Wyman-Changeux Allosteric Activation Model to Pseudo-Steady-State Responses from GABAA Receptors.
2019,
Pubmed
Stewart,
Tryptophan mutations at azi-etomidate photo-incorporation sites on alpha1 or beta2 subunits enhance GABAA receptor gating and reduce etomidate modulation.
2008,
Pubmed
,
Xenbase
Ueno,
Tryptophan scanning mutagenesis in TM2 of the GABA(A) receptor alpha subunit: effects on channel gating and regulation by ethanol.
2000,
Pubmed
,
Xenbase
Ueno,
Subunit mutations affect ethanol actions on GABA(A) receptors expressed in Xenopus oocytes.
1999,
Pubmed
,
Xenbase
Walters,
Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms.
2000,
Pubmed
,
Xenbase
Ziemba,
Correction for Inhibition Leads to an Allosteric Co-Agonist Model for Pentobarbital Modulation and Activation of α1β3γ2L GABAA Receptors.
2016,
Pubmed
,
Xenbase
