MODULATION OF HUMAN RECOMBINANT GABA(A) RECEPTORS BY PREGNANEDIOLS

Utilising two point voltage-clamp techniques on Xenopus laevis oocytes expressing human (alpha(1) beta(1) gamma(2L)) recombinant GABA(A) rec eptors, the GABA modulatory actions of six naturally occurring neurost eroids have been determined and compared with those of known positive allosteric modulators. The anaesthetic steroids 5 alpha- and 5 beta-pr egnan-3 alpha-ol-20-one produced a concentration-dependent enhancement of the GABA-evoked current. The maximal enhancement of the agonist-in duced response produced by these steroids was intermediate between tha t of pentobarbitone and diazepam, but much greater than that caused by bretazenil. For both the 5 alpha and 5 beta steroid a reduction of th e 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 or subtype (alpha(x) beta(1) gamma(2L), where x = 1, 2 or 3) for the behavioural ly active 5 alpha-pregnan-3 alpha,20 alpha-diol is also determined. Al though the maximal effect of the steroid is not influenced by the alph a 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 rela tion to the distinct behavioural actions of the neurosteroids. Copyrig ht (C) 1996 Elsevier Science Ltd