Isoflurane slows inactivation kinetics of rat recombinant alpha1beta2gamma2L GABA(A) receptors: enhancement of GABAergic transmission despite an open-channel block.
Recombinant alpha1beta2gamma2L gamma-aminobutyric acid (A) receptor (GABA(A)R) channels expressed in human embryonic kidney (HEK293) cells were used for patch-clamp experiments. The currents activated by brief pulses of GABA (10(-4) M) applied with a device for fast solution exchange to cells clamped in the whole-cell configuration mimicked GABA(A)R-mediated inhibitory postsynaptic currents. Isoflurane (ISO) at clinically relevant concentrations (0.6 mM) decreased the amplitude and prolonged the decay of the GABA-evoked response. To further detail the mechanism underlying the prolonged decay time, we made simulations based on these measurements. These simulations suggest that ISO slows the rate of GABA unbinding from the receptor. Under these conditions, ISO increases the GABA-induced charge transfer and, thus, could enhance GABAergic inhibition despite the concomitant open-channel block causing the decrease in the current amplitude.
Hapfelmeier
G
G
Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. hapfelmeier@mpipsykl.mpg.de
Haseneder
R
R
Eder
M
M
Adelsberger
H
H
Kochs
E
E
Rammes
G
G
Zieglgänsberger
W
W
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D007530:Isoflurane / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008959:Models, Neurological; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010599:Pharmacokinetics; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
D018685:Anesthetics, Inhalation; D007473:Ion Channels; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid; D007530:Isoflurane