Modulation of human recombinant GABAA receptors by pregnanediols.
Utilising two point voltage-clamp techniques on Xenopus laevis oocytes expressing human (alpha 1 beta 1 gamma 2L) recombinant GABAA receptors, the GABA modulatory actions of six naturally occurring neurosteroids have been determined and compared with those of known positive allosteric modulators. The anaesthetic steroids 5 alpha- and 5 beta-pregnan-3 alpha-ol-20-one produced a concentration-dependent enhancement of the GABA-evoked current. The maximal enhancement of the agonist-induced response produced by these steroids was intermediate between that of pentobarbitone and diazepam, but much greater than that caused by bretazenil. For both the 5 alpha and 5 beta steroid a reduction of the 20 ketone group to form either the corresponding 20 alpha or 20 beta hydroxy steroid produced, in all cases, a reduction in potency and a decrease in the maximal effect. The relationship of steroid structure to these two parameters is considered. The influence of the alpha subtype (alpha x beta 1 gamma 2L, where x = 1, 2 or 3) for the behaviourally active 5 alpha-pregnan-3 alpha,20 alpha-diol is also determined. Although the maximal effect of the steroid is not influenced by the alpha subtype, the alpha 2-containing receptor exhibits a modest decrease (approximately 6-fold) in potency compared to alpha 1- and alpha 3-containing receptors. The results described here are discussed in relation to the distinct behavioural actions of the neurosteroids.
Belelli
D
D
Department of Pharmacology and Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, U.K.
Lambert
J J
JJ
Peters
J A
JA
Gee
K W
KW
Lan
N C
NC
D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D004594:Electrophysiology; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011276:Pregnanediol / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins / Q000187:drug effects; D013256:Steroids / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D018681:Anesthetics, General; D018757:GABA Modulators; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D013256:Steroids; D011276:Pregnanediol