Competitive antagonists facilitate the recovery from desensitization of α1β2Y2 GABAA receptors expressed in Xenopus oocytes  

作　　者：Xiao-jun XU Diane ROBERTS Guo-nian ZHU Yong-chang CHANG 

机构地区：[1]Institute of Pesticide and Environmental Toxicology, Zhejiang University, Hangzhou 310029, China [2]Division of Neurobiology, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA

出　　处：《Acta Pharmacologica Sinica》2016年第8期1020-1030,共11页中国药理学报（英文版）

摘　　要：Aim： The continuous presence of an agonist drives its receptor into a refractory state, termed desensitization. In this study, we tested the hypothesis that a competitive antagonist, SR95531, could facilitate the recovery of α1β2Y2 GABAA receptor from functional desensitization. Methods： α1β2Y2 GABAA receptors were expressed in Xenopus oocytes. GABA-evoked currents were recorded using two-electrode voltage-clamp technique. Drugs were applied through perfusion. Results： Long application of GABA （100 pmol/L） evoked a large peak current followed by a small amplitude steady-state current （desensitization）. Co-application of SR95531 during the desensitization caused a larger rebound of GABA current after removal of SR95531. Furthermore, application of SR95531 after removal of GABA increased the rate of receptor recovery from desensitization, and the recovery time constant was decreased from 59±3.2 s to 33±1.6 s. SR95531-facilitated receptor recovery from desensitization was dependent on the perfusion duration of SR95531. It was also dependent on the concentration of SR95531, and the curve fitting with Hill equation revealed two potency components, which were similar to the two potency components in inhibition of the steady- state current by SR95531. Bicuculline caused similar facilitation of desensitization recovery. Conclusion： SR95531 facilitates α1β2Y2 GABAA receptor recovery from desensitization, possibly through two mechanisms： binding to the desensitized receptor and converting it to the non-desensitized state, and binding to the resting state receptor and preventing re-desensitization.Aim： The continuous presence of an agonist drives its receptor into a refractory state, termed desensitization. In this study, we tested the hypothesis that a competitive antagonist, SR95531, could facilitate the recovery of α1β2Y2 GABAA receptor from functional desensitization. Methods： α1β2Y2 GABAA receptors were expressed in Xenopus oocytes. GABA-evoked currents were recorded using two-electrode voltage-clamp technique. Drugs were applied through perfusion. Results： Long application of GABA （100 pmol/L） evoked a large peak current followed by a small amplitude steady-state current （desensitization）. Co-application of SR95531 during the desensitization caused a larger rebound of GABA current after removal of SR95531. Furthermore, application of SR95531 after removal of GABA increased the rate of receptor recovery from desensitization, and the recovery time constant was decreased from 59±3.2 s to 33±1.6 s. SR95531-facilitated receptor recovery from desensitization was dependent on the perfusion duration of SR95531. It was also dependent on the concentration of SR95531, and the curve fitting with Hill equation revealed two potency components, which were similar to the two potency components in inhibition of the steady- state current by SR95531. Bicuculline caused similar facilitation of desensitization recovery. Conclusion： SR95531 facilitates α1β2Y2 GABAA receptor recovery from desensitization, possibly through two mechanisms： binding to the desensitized receptor and converting it to the non-desensitized state, and binding to the resting state receptor and preventing re-desensitization.

关 键 词：GABAA receptor DESENSITIZATION GABA SR95531 BICUCULLINE Xenopus oocytes 

分 类 号：R[医药卫生]