Neurosteroids act on recombinant human GABAA receptors.
The endogenous steroid metabolites 3 alpha,21dihydroxy-5 alpha-pregnan-20-one and 3 alpha-hydroxy-5 alpha-pregnan-20-one potentiate GABA-activated Cl- currents recorded from a human cell line transfected with the beta 1, alpha 1 beta 1, and alpha 1 beta 1 gamma 2 combinations of human GABAA receptor subunits. These steroids are active at nanomolar concentrations in potentiating GABA-activated Cl- currents and directly elicit bicuculline-sensitive Cl- currents when applied at micromolar concentrations. The potentiating and direct actions of both steroids were expressed with every combination of subunits tested. However, an examination of single-channel currents recorded from outside-out patches excised from these transfected cells suggests that despite the common minimal structural requirements for expressing steroid and barbiturate actions, the mechanism of GABAA receptor modulation by these pregnane steroids may differ from that of barbiturates.
Puia
G
G
Fidia-Georgetown Institute for the Neurosciences, Georgetown University, Washington D.C. 20007.
Santi
M R
MR
Vicini
S
S
Pritchett
D B
DB
Purdy
R H
RH
Paul
S M
SM
Seeburg
P H
PH
Costa
E
E
D001569:Benzodiazepines / Q000494:pharmacology; D002461:Cell Line, Transformed; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002712:Chlorides / Q000378:metabolism / Q000493:pharmacokinetics / Q000502:physiology; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004553:Electric Conductivity / Q000187:drug effects / Q000502:physiology; D005445:Flunitrazepam / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000166:cytology / Q000502:physiology / Q000648:ultrastructure*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D010424:Pentobarbital / Q000494:pharmacology; D011280:Pregnanolone; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins / Q000502:physiology; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D002712:Chlorides; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D001569:Benzodiazepines; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D011280:Pregnanolone; D010424:Pentobarbital