Yang Paul, Jones Brian L, Henderson Leslie P
Dartmouth Medical School, Department of Physiology, 03755, Hanover, NH, USA.
Neuropharmacology. 2002 Sep;43(4):619-33. doi: 10.1016/s0028-3908(02)00155-7.
Modulation of GABA(A) receptors induced by both anabolic androgenic steroids (AAS) and the benzodiazepine (BZ) site agonist, zolpidem, show equivalent dependence upon gamma subunit composition suggesting that both compounds may be acting at a shared allosteric site. Here we have characterized modulation induced by the AAS, 17alpha-methyltestosterone (17alpha-MeT), for responses elicited from alpha(1)beta(3)gamma(2L) GABA(A) receptors and compared it to modulation induced by the BZ site agonists, zolpidem and diazepam. For responses elicited by brief pulses of 20 microM GABA, both the AAS and the BZ site compounds significantly increased the peak current amplitudes and total charge transfer, although 17alpha-MeT was an appreciably weaker agonist than either diazepam or zolpidem at alpha(1)beta(3)gamma(2L) receptors. 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 17alpha-MeT had no overall effect on these parameters. Experiments in which 17alpha-MeT and BZ site ligands were applied concomitantly indicated that potentiation elicited by 17alpha-MeT and zolpidem were additive and that potentiation by 17alpha-MeT could be elicited in the presence of concentrations of flumazenil that blocked BZ potentiation. Finally, kinetic modeling suggests that while effects of 17alpha-MeT can be simulated by altering receptor affinity, the data for these alpha(1)beta(3)gamma(2L) receptors were best fitted by simulations in which 17alpha-MeT increases transitions into the singly liganded open state. Taken together, our results suggest that 17alpha-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.
合成代谢雄激素类固醇（AAS）和苯二氮䓬（BZ）位点激动剂唑吡坦诱导的GABA(A)受体调节，显示出对γ亚基组成的同等依赖性，这表明这两种化合物可能作用于共同的变构位点。在此，我们已对AAS 17α-甲基睾酮（17α-MeT）诱导的α(1)β(3)γ(2L) GABA(A)受体引发的反应调节进行了表征，并将其与BZ位点激动剂唑吡坦和地西泮诱导的调节进行了比较。对于由20微摩尔GABA的短脉冲引发的反应，AAS和BZ位点化合物均显著增加了峰值电流幅度和总电荷转移，尽管在α(1)β(3)γ(2L)受体上，17α-MeT是比地西泮或唑吡坦明显更弱的激动剂。两类调节剂均未增强毫摩尔浓度GABA引发反应的峰值电流幅度。BZ位点化合物改变了失活、脱敏以及从脱敏恢复的时间常数，然而17α-MeT对这些参数没有总体影响。同时应用17α-MeT和BZ位点配体的实验表明，17α-MeT和唑吡坦引发的增强作用是相加的，并且在存在阻断BZ增强作用的氟马西尼浓度时，17α-MeT仍可引发增强作用。最后，动力学建模表明，虽然17α-MeT的作用可以通过改变受体亲和力来模拟，但这些α(1)β(3)γ(2L)受体的数据通过模拟17α-MeT增加向单配体开放状态的转变能得到最佳拟合。综上所述，我们的结果表明，17α-MeT并不作用于高亲和力的BZ位点，而是可能在低亲和力BZ位点或新位点引发其一些效应。
