The influence of subunit composition on the interaction of neurosteroids with GABAA receptors
The influence of subunit composition on the interaction of neurosteroids with GABAA receptors
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DOI：
10.1016/s0028-3908(02)00172-7
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发表时间：
2002-09-01
影响因子：
4.7
通讯作者：
Lambert, JJ
中科院分区：
文献类型：
--
作者：
Belelli, D;Casula, A;Lambert, JJ
The influence of the subunit composition of human GABA(A) receptors upon the GABA-modulatory properties of 5alpha-pregnan-3alpha-ol-20-one (5alpha,3alpha) has been examined using the Xenopus laevis oocyte expression system and the two electrode voltage-clamp technique. Steroid potency (EC50) is modestly influenced by the alpha-isoform. (alpha(x)beta(1)gamma(2L) ; x = 1-6). alpha(2)-, alpha(4)- and alpha(5)-containing receptors are significantly less sensitive to the action of low concentrations of 5alpha,3alpha (10-100 nM) when compared to alpha(1,3,6)beta(1)gamma(2L) receptors. Additionally, the maximal effect of the steroid is favoured at alpha(6)-containing receptors. The beta-isoform (alpha(1)beta(gamma)gamma(2L); gamma = 1-3) has little influence on the GABA-modulatory effect of the neurosteroid. The EC50 of 5alpha,3alpha is only modestly influenced by the omission of the gamma(2) subunit (alpha(1)beta(1)gamma(2L) vs alpha(1)beta(1)): while the maximal effect is favoured by the binary complex. However, the identity of the gamma subunit influences the GABA(A)-modulatory potency of 5alpha,3alpha with gamma(2)- and gamma(1)-containing receptors being the most and the least sensitive to 5alpha,3alpha, respectively. Finally, incorporation of the epsilon or delta subunit dramatically reduces and augments the GABA-enhancing actions of the steroid, respectively. These findings provide evidence that 5a,3a discrivainates amongst recombinant receptors of varied subunit composition. Furthermore, this selectivity may contribute to their neuronal specificity and behavioural profile. (C) 2002 Elsevier Science Ltd. All rights reserved.
