Bianchi Matt T, Botzolakis Emmanuel J, Lagrange Andre H, Macdonald Robert L
Sleep Disorders Center, Beth Israel Deaconess Medical Center, Boston, MA, United States.
Epilepsy Res. 2009 Aug;85(2-3):212-20. doi: 10.1016/j.eplepsyres.2009.03.007. Epub 2009 May 15.
Benzodiazepines (BDZs) are GABA(A) receptor modulators with anxiolytic, hypnotic, and anticonvulsant properties. BDZs are understood to potentiate GABA(A) receptor function by increasing channel opening frequency, in contrast to barbiturates, which increase channel open duration. However, the in vitro evidence demonstrating increased opening frequency involved prolonged exposure to sub-saturating GABA concentrations, conditions most similar to those found in extrasynaptic areas. In contrast, synaptic GABA(A) receptors are transiently activated by high GABA concentrations. To determine if BDZ modulation of single-channel opening frequency would be different for BDZ-sensitive receptors activated under synaptic versus extrasynaptic conditions, a combination of patch clamp recording and kinetic modeling was used. Consistent with the original experimental findings, BDZs were found to increase receptor affinity for GABA by decreasing the unbinding rate. While this mechanism was predicted to increase opening frequency under extrasynaptic conditions, simulations predicted that the same mechanism under synaptic conditions would increase the number, but not the frequency, of single-channel openings. Thus, a single mechanism (slower GABA unbinding) can produce differential changes in opening frequency under synaptic versus extrasynaptic conditions. The functional impact of BDZs on GABA(A) receptors therefore depends upon the physiological context of receptor activation.
苯二氮䓬类药物（BDZs）是γ-氨基丁酸A型（GABA(A)）受体调节剂，具有抗焦虑、催眠和抗惊厥特性。与增加通道开放持续时间的巴比妥类药物不同，BDZs被认为是通过增加通道开放频率来增强GABA(A)受体功能。然而，体外证据表明，增加开放频率涉及长时间暴露于亚饱和GABA浓度下，这种条件与突触外区域的条件最为相似。相比之下，突触GABA(A)受体由高浓度GABA短暂激活。为了确定BDZ对单通道开放频率的调节在突触和突触外条件下激活的BDZ敏感受体是否不同，采用了膜片钳记录和动力学建模相结合的方法。与最初的实验结果一致，发现BDZs通过降低解离速率来增加受体对GABA的亲和力。虽然预计这种机制会在突触外条件下增加开放频率，但模拟预测在突触条件下相同机制会增加单通道开放的数量，而不是频率。因此，单一机制（较慢的GABA解离）在突触和突触外条件下可产生开放频率的差异变化。因此，BDZs对GABA(A)受体的功能影响取决于受体激活的生理背景。
