Positive modulation of human gamma-aminobutyric acid type A and glycine receptors by the inhalation anesthetic isoflurane.
The interactions of the inhalation anesthetic agent isoflurane with ligand-gated chloride channels were studied using transient expression of recombinant human receptors in a mammalian cell line. Isoflurane enhanced gamma-aminobutyric acid (GABA)-activated chloride currents in cells that expressed heteromeric GABAA receptors consisting of combinations of alpha 1 or alpha 2, beta 1, and gamma 2 subunits and in cells that expressed receptors consisting of combinations of only alpha and beta subunits. Receptors consisting of alpha 2 and gamma 2 subunits were poorly expressed but were sensitive to isoflurane. Receptors consisting of beta 1 and gamma 2 subunits were not expressed. Isoflurane also enhanced glycine-activated chloride currents through homomeric alpha glycine receptors but did not enhance GABA currents in cells expressing homomeric rho 1 receptors. These results show that not all ligand-gated chloride channel receptors are sensitive to isoflurane and, therefore, that the anesthetic interacts with specific structural determinants of these ion channel proteins.
Harrison
N L
NL
Department of Pharmacological and Physiological Sciences, University of Chicago, Illinois 60637.
Kugler
J L
JL
Jones
M V
MV
Greenblatt
E P
EP
Pritchett
D B
DB
D000595:Amino Acid Sequence; D002460:Cell Line; D018118:Chloride Channels; D006801:Humans; D015640:Ion Channel Gating; D007473:Ion Channels / Q000187:drug effects*; D007530:Isoflurane / Q000494:pharmacology*; D008565:Membrane Proteins / Q000187:drug effects*; D008969:Molecular Sequence Data; D011963:Receptors, GABA-A / Q000187:drug effects*; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D011994:Recombinant Proteins / Q000187:drug effects; D017386:Sequence Homology, Amino Acid
D018118:Chloride Channels; D007473:Ion Channels; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; D011994:Recombinant Proteins; D007530:Isoflurane