Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Anesthesiology
2008 Jan 01;1081:103-12. doi: 10.1097/01.anes.0000296074.33999.52.
Show Gene links
Show Anatomy links
Photo-activated azi-etomidate, a general anesthetic photolabel, irreversibly enhances gating and desensitization of gamma-aminobutyric acid type A receptors.
Zhong H
,
Rüsch D
,
Forman SA
.
???displayArticle.abstract???
The general anesthetic etomidate acts via gamma-aminobutyric acid type A (GABA(A)) receptors, enhancing activation at low GABA and prolonging deactivation. Azi-etomidate is a photo-reactive etomidate derivative with similar pharmacological actions, which has been used to identify putative binding sites. The authors examine the irreversible effects of azi-etomidate photo-modification on functional GABA(A) receptors in cell membranes. GABA(A) receptors (alpha1beta2gamma2L) were expressed in both Xenopus oocytes and human embryonic kidney cells exposed to 365 nm light-activated azi-etomidate with or without GABA, then extensively washed. Receptor-mediated chloride currents were measured using voltage clamp electrophysiology to assess the ratio of peak responses at 10 microm and 1 mm GABA (I10/I1000) and deactivation time course. After azi-etomidate photo-modification, I10/I1000 ratios were persistently enhanced and deactivation was prolonged, mimicking reversible azi-etomidate actions. Azi-etomidate and ultraviolet light were required to produce irreversible receptor modulation. Adding GABA during photo-modification greatly enhanced irreversible modulation. Azi-etomidate modification also dose-dependently reduced maximal GABA-activated currents, consistent with accumulation of permanently desensitized receptors. Excess etomidate during azi-etomidate photo-modification competitively reduced permanent desensitization. Persistent channel modulation was blocked by 320-fold excess etomidate but enhanced when 32-fold excess etomidate was present. Azi-etomidate efficiently photo-modifies etomidate sites on GABA(A) receptors in intact cells, producing persistent functional changes that mimic its reversible effects. The results demonstrate sequential modification at more than one etomidate site per receptor. The sites display reciprocal positive cooperativity. In combination with focal photo-activation, azi-etomidate may prove useful for studies of anesthetic actions in neural circuits.
Absalom,
Mechanisms of channel gating of the ligand-gated ion channel superfamily inferred from protein structure.
2004, Pubmed
Absalom,
Mechanisms of channel gating of the ligand-gated ion channel superfamily inferred from protein structure.
2004,
Pubmed
Akk,
Neuroactive steroids have multiple actions to potentiate GABAA receptors.
2004,
Pubmed
Arden,
Increased sensitivity to etomidate in the elderly: initial distribution versus altered brain response.
1986,
Pubmed
Ashton,
Modulation of a GABA-ergic inhibitory circuit in the in vitro hippocampus by etomidate isomers.
1985,
Pubmed
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
Belelli,
The in vitro and in vivo enantioselectivity of etomidate implicates the GABAA receptor in general anaesthesia.
2003,
Pubmed
,
Xenbase
Brown,
Specific labeling and permanent activation of the retinal rod cGMP-activated channel by the photoaffinity analog 8-p-azidophenacylthio-cGMP.
1993,
Pubmed
Campagna-Slater,
Anaesthetic binding sites for etomidate and propofol on a GABAA receptor model.
2007,
Pubmed
Chang,
Positive allosteric modulation by ultraviolet irradiation on GABA(A), but not GABA(C), receptors expressed in Xenopus oocytes.
2001,
Pubmed
,
Xenbase
Eisenman,
Anticonvulsant and anesthetic effects of a fluorescent neurosteroid analog activated by visible light.
2007,
Pubmed
Forman,
Photoactivated 3-azioctanol irreversibly desensitizes muscle nicotinic ACh receptors via interactions at alphaE262.
2007,
Pubmed
,
Xenbase
Forman,
A hydrophobic photolabel inhibits nicotinic acetylcholine receptors via open-channel block following a slow step.
1999,
Pubmed
Grasshoff,
Molecular and systemic mechanisms of general anaesthesia: the 'multi-site and multiple mechanisms' concept.
2005,
Pubmed
He,
Probing the interactions between cAMP and cGMP in cyclic nucleotide-gated channels using covalently tethered ligands.
2001,
Pubmed
,
Xenbase
Hill-Venning,
Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor.
1997,
Pubmed
,
Xenbase
Hosie,
Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites.
2006,
Pubmed
Husain,
2-(3-Methyl-3H-diaziren-3-yl)ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate: a derivative of the stereoselective general anesthetic etomidate for photolabeling ligand-gated ion channels.
2003,
Pubmed
,
Xenbase
Jurd,
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.
2003,
Pubmed
Leite,
Conformation-dependent hydrophobic photolabeling of the nicotinic receptor: electrophysiology-coordinated photochemistry and mass spectrometry.
2003,
Pubmed
Li,
Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog.
2006,
Pubmed
Liao,
R (+) etomidate and the photoactivable R (+) azietomidate have comparable anesthetic activity in wild-type mice and comparably decreased activity in mice with a N265M point mutation in the gamma-aminobutyric acid receptor beta3 subunit.
2005,
Pubmed
McKernan,
Which GABAA-receptor subtypes really occur in the brain?
1996,
Pubmed
MONOD,
ON THE NATURE OF ALLOSTERIC TRANSITIONS: A PLAUSIBLE MODEL.
1965,
Pubmed
Moody,
Distinct loci mediate the direct and indirect actions of the anesthetic etomidate at GABA(A) receptors.
1997,
Pubmed
Mourot,
Probing the reorganization of the nicotinic acetylcholine receptor during desensitization by time-resolved covalent labeling using [3H]AC5, a photoactivatable agonist.
2006,
Pubmed
O'Meara,
The GABA-A beta3 subunit mediates anaesthesia induced by etomidate.
2004,
Pubmed
Reynolds,
Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms.
2003,
Pubmed
Rüsch,
Classic benzodiazepines modulate the open-close equilibrium in alpha1beta2gamma2L gamma-aminobutyric acid type A receptors.
2005,
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
Sanna,
Differential subunit dependence of the actions of the general anesthetics alphaxalone and etomidate at gamma-aminobutyric acid type A receptors expressed in Xenopus laevis oocytes.
1997,
Pubmed
,
Xenbase
Scheller,
Coupled and uncoupled gating and desensitization effects by pore domain mutations in GABA(A) receptors.
2002,
Pubmed
Siegwart,
Molecular determinants for the action of general anesthetics at recombinant alpha(2)beta(3)gamma(2)gamma-aminobutyric acid(A) receptors.
2002,
Pubmed
Steinbach,
Modulation of GABA(A) receptor channel gating by pentobarbital.
2001,
Pubmed
Tomlin,
Stereoselective effects of etomidate optical isomers on gamma-aminobutyric acid type A receptors and animals.
1998,
Pubmed
Uchida,
Etomidate potentiation of GABAA receptor gated current depends on the subunit composition.
1995,
Pubmed
Yang,
Mechanisms of etomidate potentiation of GABAA receptor-gated currents in cultured postnatal hippocampal neurons.
1996,
Pubmed
