Author: Hall, A.C.; Stevens, R.J.N.; Betts, B.A.; Yeung, W.-Y.; Kelley, J.C.; Harrison, N.L.
Description: The volatile anesthetic isoflurane both prolongs and reduces the amplitude of GABA-mediated inhibitory postsynaptic currents (IPSCs) recorded in neurons. To explore the latter effect, we investigated isoflurane-induced inhibition of steady-state desensitized GABA currents in Xenopus oocytes expressing wild-type alpha(1)beta(2), alpha(1)beta(2)gamma(2s), mutant alpha(1)(S270H)beta(2) (serine to histidine at residue 270) or alpha(1)(S270H)beta(2)gamma(2s) receptors. The alpha(1) serine 270 site in TM2 (second transmembrane domain of the subunit) is postulated as a binding site for some volatile agents and is critical for positive modulation of sub-maximal GABA responses by isoflurane. For all receptor combinations, at < or =0.6 mM isoflurane (< or =2 minimum alveolar concentration (MAC)) current inhibitions were not pronounced ( approximately 10%) with block reaching half-maximal levels at supraclinical concentrations ( approximately 2 mM isoflurane, 6 MAC). Comparisons with other GABA(A) receptor blockers indicated that isoflurane blocks in a similar manner to picrotoxin, possibly via the pore of the receptor. The extent of isoflurane-induced inhibition was significantly attenuated by inclusion of the gamma(2s)-subunit but was unaffected by introduction of the S270H mutation in the alpha(1)-subunit. In conclusion, isoflurane binds with low affinity and with subunit-specificity to an inhibitory site on the GABA(A) receptor that is distinct from the site that facilitates positive modulation at the extracellular end of the pore.
Subject headings: Anesthetics, Inhalation/pharmacology; Animals; Bicuculline/pharmacology; Dose-Response Relationship, Drug; Excitatory Postsynaptic Potentials/drug effects/physiology; GABA Antagonists/pharmacology; Isoflurane/pharmacology; Membrane Potentials/drug effects/physiology; Mutation; Oocytes/drug effects; Patch-Clamp Techniques; Picrotoxin/pharmacology; Protein Subunits/drug effects/metabolism; Receptors, GABA-A/drug effects/genetics/metabolism; Recombinant Proteins/drug effects; Substrate Specificity; Xenopus
Publication year: 2005
Journal or book title: Neuroscience Letters
Volume: 382
Issue: 3
Pages: 332-337
Find the full text : http://www.sciencedirect.com/science/article/pii/S0304394005003228
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Type: Journal Article
Serial number: 507