Author: Hall, A.C.; Rowan, K.C.; Stevens, R.J.N.; Kelley, J.C.; Harrison, N.L.
Description: gamma-aminobutyric acid type A receptors (GABA(A)-R) mediate synaptic inhibition and meet many pharmacological criteria required of important general anesthetic targets. During synaptic transmission GABA release is sufficient to saturate, maximally activate, and transiently desensitize postsynaptic GABA(A)-Rs. The resulting inhibitory postsynaptic currents (IPSCs) are prolonged by volatile anesthetics like isoflurane. We investigated the effects of isoflurane on maximally activated and desensitized GABA(A)-R currents expressed in Xenopus oocytes. Wild-type alpha(1)beta(2) and alpha(1)beta(2)gamma(2s) receptors were exposed to 600 microM GABA until currents reached a steady-state desensitized level. At clinical concentrations (0.02-0.3 mM), isoflurane produced a dose-dependent enhancement of steady-state desensitized current in alpha(1)beta(2) receptors, an effect that was less apparent in receptors including a gamma(2s)-subunit. When serine at position 270 is mutated to histidine (alpha(1)(S270H)) in the second transmembrane segment of the alpha(1)-subunit, the currents evoked by sub-saturating concentrations of GABA became less sensitive to isoflurane enhancement. In addition, isoflurane enhancements of desensitized currents were greatly attenuated by this mutation and were undetectable in alpha(1)(S270H)beta(2)gamma(2s) receptors. In conclusion, isoflurane enhancement of GABA(A)-R currents evoked by saturating concentrations of agonist is subunit-dependent. The effects of isoflurane on desensitized receptors may be partly responsible for the prolongation of IPSCs during anesthesia.
IMPLICATIONS: Isoflurane enhances desensitized gamma-aminobutyric acid type A receptor (GABA(A)-R) currents, an effect that is subunit-dependent and attenuated by a mutation in an alpha(1)-subunit pore residue of the GABA(A)-R. As GABA release at inhibitory synapses is typically saturating, isoflurane modulation of desensitized receptors may be partly responsible for prolongation of inhibitory postsynaptic currents during anesthesia.
Subject headings: Anesthetics, Inhalation/pharmacology; Animals; DNA, Complementary/drug effects/genetics; Dose-Response Relationship, Drug; Humans; Isoflurane/pharmacology; Kinetics; Mutation/genetics/physiology; Oocytes/metabolism; Receptors, GABA-A/drug effects/genetics; Xenopus
Publication year: 2004
Journal or book title: Anesthesia and Analgesia
Volume: 98
Issue: 5
Pages: 1297-1304
Find the full text : http://journals.lww.com/anesthesia-analgesia/Abstract/2004/05000/The_Effects_of_Isoflurane_on_Desensitized.21.aspx
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Type: Journal Article
Serial number: 506