Mechanisms of anabolic androgenic steroid modulation of alpha(1)beta(3)gamma(2L) GABA(A) receptors.
Mechanisms of anabolic androgenic steroid modulation of alpha(1)beta(3)gamma(2L) GABA(A) receptors.
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α(1)β(3)gamma(2L) GABA(A) 受体的合成代谢雄激素类固醇调节机制。
DOI：
10.1016/s0028-3908(02)00155-7
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发表时间：
2002
影响因子：
4.7
通讯作者：
Henderson,LeslieP
中科院分区：
文献类型：
--
作者：
Yang,Paul;Jones,BrianL;Henderson,LeslieP
Modulation of GABAAreceptors induced by both anabolic androgenic steroids (AAS) and the benzodiazepine (BZ) site agonist, zolpidem, show equivalent dependence upon γ subunit composition suggesting that both compounds may be acting at a shared allosteric site. Here we have characterized modulation induced by the AAS, 17α-methyltestosterone (17α-MeT), for responses elicited from α1β3γ2LGABAAreceptors and compared it to modulation induced by the BZ site agonists, zolpidem and diazepam. For responses elicited by brief pulses of 20 μM GABA, both the AAS and the BZ site compounds significantly increased the peak current amplitudes and total charge transfer, although 17α-MeT was an appreciably weaker agonist than either diazepam or zolpidem at α1β3γ2Lreceptors. Neither class of modulator enhanced peak current amplitudes for responses elicited by mM concentrations of GABA. BZ site compounds altered time constants of deactivation, desensitization, and recovery from desensitization, however 17α-MeT had no overall effect on these parameters. Experiments in which 17α-MeT and BZ site ligands were applied concomitantly indicated that potentiation elicited by 17α-MeT and zolpidem were additive and that potentiation by 17α-MeT could be elicited in the presence of concentrations of flumazenil that blocked BZ potentiation. Finally, kinetic modeling suggests that while effects of 17α-MeT can be simulated by altering receptor affinity, the data for these α1β3γ2Lreceptors were best fitted by simulations in which 17α-MeT increases transitions into the singly liganded open state. Taken together, our results suggest that 17α-MeT does not act at the high-affinity BZ site, but may elicit some of its effects at the low affinity BZ site or at a novel site.
