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Determinants of the Sensitivity of AMPA Receptors to Xenon Andrew J Anesthesiology 2004; 100:347–58 © 2004 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Determinants of the Sensitivity of AMPA Receptors to Xenon Andrew J. R. Plested, Ph.D.,* Scott S. Wildman, Ph.D.,† William R. Lieb, Ph.D.,‡ Nicholas P. Franks, Ph.D.§ Background: There is substantial and growing literature on antagonists has been used as support for this view. the actions of general anesthetics on a variety of neurotrans- Moreover, there is clear evidence that excitatory synap- mitter-gated ion channels, with the greatest attention being ␥ tic transmission can be substantially affected by clinically focused on inhibitory -amino butyric acid type A receptors. In 4–8 contrast, glutamate receptors, the most important class of fast relevant concentrations of anesthetics. However, excitatory neurotransmitter-gated receptor channels, have re- even for closely related anesthetics, different responses ceived much less attention, and their role in the production of have been reported, with some investigators showing4,9 the anesthetic state remains controversial. that pentobarbital strongly inhibits excitatory synaptic ␣ Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/100/2/347/354478/0000542-200402000-00025.pdf by guest on 25 September 2021 Methods: -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic 10 acid (AMPA) receptors formed from a variety of different sub- transmission, whereas others report that thiopental units were expressed in Xenopus oocytes and HEK-293 cells, causes no significant inhibition. Similarly disparate re- and their sensitivities to the inhalational general anesthetics sults have been obtained with inhalational anesthetics. xenon, isoflurane, and halothane were determined using two- For example, some studies have found no effects on electrode voltage clamp and patch clamp techniques. The ef- stimulus-evoked excitatory responses11,12 in rat hip- fects of desensitization on anesthetic sensitivity were investi- 6,8 gated using cyclothiazide and site-directed mutagenesis. An pocampus, whereas others have found that excitatory ultrarapid application system was also used to mimic rapid postsynaptic potential amplitudes are significantly af- high-concentration glutamate release at synapses. fected. These disparate findings may be a consequence Results: The authors show that xenon can potently inhibit of both different experimental techniques and prepara- AMPA receptors when assayed using bath application of kai- tions, but whatever the reason, the sensitivity of excita- nate. However, when the natural neurotransmitter L-glutamate is used under conditions in which the receptor desensitization tory transmission to anesthetics remains uncertain. is blocked and the peak of the glutamate-activated response can Even in cases in which anesthetic inhibition of excita- be accurately measured, the pattern of inhibition changes tory synaptic conduction seems unambiguous, it has markedly. When desensitization is abolished by a single-point generally not been possible to determine whether the mutation (L497Y in GluR1 and the equivalent mutation L505Y in GluR4), the xenon inhibition is eliminated. When AMPA recep- primary targets are presynaptic, postsynaptic, or both. tors are activated by glutamate using an ultrarapid application One potentially direct approach would be to determine system that mimics synaptic conditions, sensitivity to xenon, the effects of anesthetics on defined glutamate receptor halothane, and isoflurane is negligible. subtypes expressed in in vitro expression systems. In- Conclusions: AMPA receptors, when assayed in heterologous deed, there have been several articles13–18 reporting the expression systems, showed a sensitivity to inhalational anes- thetics that was minimal when glutamate was applied rapidly at results of such studies, but, as with the synaptic systems, high concentrations. Because these are the conditions that are a complex picture emerges. Some studies report signif- most relevant to synaptic transmission, the authors conclude icant inhibition, whereas others report insensitivity; that AMPA receptors are unlikely to play a major role in the however, this depends on both the general anesthetic production of the anesthetic state by inhalational agents. studied and the receptor subunit composition. Impor- tantly, it has also been shown that anesthetic sensitivity IONOTROPIC glutamate receptors underlie the majority can depend greatly on the neurotransmitter agonist of fast excitatory synaptic transmission in the mamma- used.4,19 While glutamate is the major neurotransmitter lian central nervous system. It has long been thought released at excitatory synapses, postsynaptic glutamate that the excitatory synaptic conduction mediated by receptors are categorized according to both sequence these glutamate receptors may be an important target for homology and their sensitivity to artificial agonists: N- 1 general anesthetics. The profound reduction in whole- methyl-D-aspartate (NMDA), kainic acid, and ␣-amino-3- 2,3 animal anesthetic requirement that is observed when hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). anesthetics are coadministered with glutamate receptor The subject of this article is the anesthetic sensitivity of AMPA receptors (AMPARs). These receptors are proba- bly tetramers20 formed from combinations of four sub- * Research Student. Current position: Department of Pharmacology, University units (GluR1–4) and give rise to the fast current compo- College London, London, United Kingdom. † Research Associate. Current po- sition: Department of Physiology, Royal Free and University College Medical nent at glutamatergic synapses. Functional heterogeneity School, London, United Kingdom. ‡ Professorial Research Fellow, § Professor of native AMPARs is generated not only by variable of Biophysics and Anesthetics. subunit stoichiometry, but also by the existence of splice Received from the Biophysics Section, The Blackett Laboratory, Imperial 21 College London, London, United Kingdom. Submitted for publication August 4, variants and posttranscriptional RNA editing. 2003. Accepted for publication October 6, 2003. Supported by grants from the Although AMPARs can, by definition, be activated se- Medical Research Council, London, United Kingdom, and Carburos Metálicos, Madrid, Spain. Dr. Plested received a Medical Research Council Studentship. lectively by AMPA, they can also be activated by kainate 22 Address reprint requests to Dr. Franks: Biophysics Section, The Blackett (which is a partial agonist ) as well as, of course, gluta- Laboratory, Imperial College London, London SW7 2AZ, United Kingdom. Ad- dress electronic mail to: [email protected]. Individual article reprints may be mate. The application of glutamate to isolated receptors 23 purchased through the Journal Web site, www.anesthesiology.org. leads to an extremely rapidly desensitizing response, with Anesthesiology, V 100, No 2, Feb 2004 347 348 PLESTED ET AL. a time course of the order of milliseconds. It has been Netherlands). A pair of short (25–45 bases) complemen- common practice, when assessing the pharmacologic sen- tary oligonucleotide primers, incorporating the intended sitivity of glutamate receptors, to use artificial agonists such mutation, was synthesized (MWG-Biotech, Ebersberg, as kainate, which elicit much slower, nondesensitizing re- Germany). To aid identification of successful mutants, a sponses that are experimentally more convenient to mea- silent restriction site was included in the primer se- sure and easier to record. The use of artificial agonists that quence. Mutant DNA constructs were sequenced (MWG- give responses with kinetics that are very different from Biotech) to confirm the introduction of the correct mu- those of the natural neurotransmitter, although undoubt- tated bases. edly convenient, runs the risk that their inhibition by anes- For transient transfection into mammalian cells, AMPAR thetics, or any other drug for that matter, may not accu- cDNAs encoding GluR1 (flip) and GluR4 (flip) were rately reflect their sensitivity when glutamate is used as the subcloned into a vector containing a cytomegalovirus Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/100/2/347/354478/0000542-200402000-00025.pdf by guest on 25 September 2021 agonist. promoter (pcDNA 3.1; Invitrogen, Paisley, United King- In previous work from this laboratory,24,25 we have dom). The start codon was placed in strong context by shown that the “inert” gas xenon has little or no effect substituting an optimal Kozak sequence.28 Constructs on ␥-amino butyric acid type A receptors (which are were sequenced to ensure the correct orientation and sensitive26 to most other general anesthetics) but is an identity of the insert in each case. apparently selective blocker of the NMDA subtype of glutamate receptors. At a concentration that causes gen- Preparation of Xenopus Oocytes eral anesthesia in humans (approximately 70% of 1 at- Adult female Xenopus laevis frogs (Blades Biological, mosphere [atm]), xenon inhibited the slow component Cowden, Kent, United Kingdom), maintained in fresh- of the excitatory postsynaptic currents, which can be water holding tanks at 20°–22°C, were anesthetized by identified as being mediated by NMDA receptors, while immersion in a 0.2% (weight/volume) solution of tric- having no effect on the fast component of the response, aine (3-aminobenzoic acid ethyl ester, methanesulfonate which can be identified as being due to AMPARs. Sub- salt). Portions of the ovaries
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