Subunit-dependent block by isoflurane of wild-type and mutant α1S270H GABAA receptor currents in Xenopus oocytes
| Autor: | Renna J.N. Stevens, Wing-Yee Yeung, Jill C. Kelley, Neil L. Harrison, Adam C. Hall, Brooke A. Betts |
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| Rok vydání: | 2005 |
| Předmět: |
Patch-Clamp Techniques
Xenopus Pharmacology Bicuculline Inhibitory postsynaptic potential Membrane Potentials Substrate Specificity GABA Antagonists chemistry.chemical_compound medicine Animals Picrotoxin Receptor Dose-Response Relationship Drug Isoflurane GABAA receptor General Neuroscience Excitatory Postsynaptic Potentials GABA receptor antagonist Receptors GABA-A Molecular biology Recombinant Proteins Protein Subunits chemistry Anesthetics Inhalation Mutation Oocytes Excitatory postsynaptic potential medicine.drug |
| Zdroj: | Neuroscience Letters. 382:332-337 |
| ISSN: | 0304-3940 |
| DOI: | 10.1016/j.neulet.2005.03.029 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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