Auxiliary GABAB Receptor Subunits Uncouple G Protein βγ Subunits from Effector Channels to Induce Desensitization
Auxiliary GABAB Receptor Subunits Uncouple G Protein βγ Subunits from Effector Channels to Induce Desensitization
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DOI：
10.1016/j.neuron.2014.04.015
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发表时间：
2014-06-04
期刊：
影响因子：
16.2
通讯作者：
Bettler, Bernhard
中科院分区：
文献类型：
--
作者：
Turecek, Rostislav;Schwenk, Jochen;Bettler, Bernhard
G 蛋白 β γ 亚基激活 K+ 通道是 G 蛋白偶联受体的重要信号传导机制。通常，受体激活的 K+ 电流在激动剂持续存在的情况下会脱敏，以避免对细胞活动产生过度影响。辅助 GABA(B) 受体亚基 KCTD12 诱导 K+ 电流反应快速且明显的脱敏。使用蛋白质组学和电生理学方法，我们现在表明 KCTD12 诱导的脱敏是由与 G 蛋白的双重相互作用造成的：组成型结合稳定了受体上的异三聚体 G 蛋白，而与受体激活的 G beta gamma 亚基的动态结合通过将 G beta gamma 与效应器 K+ 通道解偶联来诱导脱敏。虽然无受体的 KCTD12 可以使体外其他 GPCR 激活的 K+ 电流脱敏，但天然 KCTD12 只与 GABA(B) 受体相关。因此，KCTD12 的基因消除会特异性改变大脑中的 GABA(B) 反应。我们的结果表明，通过利用截获 G beta gamma 信号传导的 KCTD12，GABA(B) 受体具有快速且可逆的脱敏作用。
Activation of K+ channels by the G protein beta gamma subunits is an important signaling mechanism of G-protein-coupled receptors. Typically, receptor-activated K+ currents desensitize in the sustained presence of agonists to avoid excessive effects on cellular activity. The auxiliary GABA(B) receptor subunit KCTD12 induces fast and pronounced desensitization of the K+ current response. Using proteomic and electrophysiological approaches, we now show that KCTD12-induced desensitization results from a dual interaction with the G protein: constitutive binding stabilizes the heterotrimeric G protein at the receptor, whereas dynamic binding to the receptor-activated G beta gamma subunits induces desensitization by uncoupling G beta gamma from the effector K+ channel. While receptor-free KCTD12 desensitizes K+ currents activated by other GPCRs in vitro, native KCTD12 is exclusively associated with GABA(B) receptors. Accordingly, genetic ablation of KCTD12 specifically alters GABA(B) responses in the brain. Our results show that GABA(B) receptors are endowed with fast and reversible desensitization by harnessing KCTD12 that intercepts G beta gamma signaling.