Yang Paul, Jones Brian L, Henderson Leslie P
Department of Physiology, Dartmouth Medical School, Hanover, NH 03755, USA.
Neuropharmacology. 2005 Sep;49(3):300-16. doi: 10.1016/j.neuropharm.2005.03.017.
Neural transmission mediated by circuits expressing alpha2 subunit-containing gamma-aminobutyric acid type A (GABA(A)) receptors is critical for the expression of behaviors known to be altered by anabolic androgenic steroids (AAS). Here we show that micromolar concentrations of AAS, which reflect levels found in steroid abusers, induce positive modulation of currents from alpha2beta3 gamma2L recombinant receptors elicited by pulses of GABA that mimic synaptic conditions in a manner that is mechanistically distinct from modulation induced at alpha1beta3 gamma2L receptors. Specifically, at alpha2-containing receptors, the AAS, 17alpha-methyltestosterone (17alpha-MeT) enhanced peak current, slowed deactivation, diminished desensitization, and promoted entry of receptors into more distal states along the activation pathway. Analysis of GABA(A) receptor-mediated synaptic currents in primary cortical neurons followed by single cell real-time RT-PCR demonstrated that 17alpha-MeT enhancement of synaptic currents is proportional to the ratio of alpha2 to alpha1 subunit mRNA. Finally, we show that the modulation elicited by AAS is not comparable to that produced by micromolar concentrations of other positive allosteric modulators at alpha2-containing receptors. In sum, these data indicate that AAS elicit effects on GABA(A) receptor function that depend significantly on alpha subunit composition and that the mechanism of AAS modulation of GABA(A) receptors is distinct from that of other positive allosteric modulators.
由表达含α2亚基的γ-氨基丁酸A型（GABA(A)）受体的神经回路介导的神经传递，对于已知会因合成代谢雄激素类固醇（AAS）而改变的行为的表达至关重要。我们在此表明，微摩尔浓度的AAS（反映类固醇滥用者体内的水平），会以一种与在α1β3γ2L受体上诱导的调节机制不同的方式，对模拟突触条件的γ-氨基丁酸脉冲引发的α2β3γ2L重组受体电流产生正向调节作用。具体而言，在含α2的受体上，AAS 17α-甲基睾酮（17α-MeT）增强了峰值电流，减缓了失活过程，减少了脱敏现象，并促使受体沿着激活途径进入更远端的状态。对原代皮质神经元中GABA(A)受体介导的突触电流进行分析，随后进行单细胞实时逆转录-聚合酶链反应，结果表明17α-MeT对突触电流的增强作用与α2和α1亚基mRNA的比例成正比。最后，我们表明AAS引发的调节作用与含α2的受体上微摩尔浓度的其他正向变构调节剂所产生的调节作用不可比。总之，这些数据表明，AAS对GABA(A)受体功能的影响在很大程度上取决于α亚基的组成，并且AAS对GABA(A)受体的调节机制与其他正向变构调节剂的调节机制不同。
