Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors
Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors
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DOI：
10.1113/jphysiol.2009.182444
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发表时间：
2010-04-15
影响因子：
5.5
通讯作者：
Smart, Trevor G.
中科院分区：
文献类型：
--
作者：
Mortensen, Martin;Ebert, Bjarke;Smart, Trevor G.
突触和突触外GABA（A）受体的激活特性对于形成中枢神经系统中的阶段性和紧张性抑制的特征是重要的，这将对神经元网络的活动产生关键影响。在这里，我们研究了三种激动剂，GABA，蝇蕈醇和4，5，6，7-四氢异恶唑并[5，4-c]吡啶-3（2 H）-酮（THIP）的活性，以进一步了解海马和丘脑中表达的典型突触和突触外型受体的α 1 β 3 γ 2，α 4 β 3 γ 2和α 4 β 3 δ受体的激活概况。激动剂显示效力的顺序在三种受体之间是不变的，这主要取决于激动剂解离常数。在含有δ亚基的突触外型GABA（A）受体，THIP和蝇蕈醇还表现出不同程度的超激动剂行为。通过比较激动剂诱导的全细胞和单通道电流，我们为它们不同的激活模式提供了分子解释。对于高浓度的THIP，对α 4 β 3 δ受体的不寻常的超激动剂行为是其增加较长通道开放的持续时间及其频率的能力的结果，从而导致较长的爆发持续时间。相比之下，蝇蕈醇，适度的超激动剂的行为所造成的减少脱敏的突触外型受体。通过选择的外源激动剂特异性地增加受体激活的功效的能力超过用天然递质获得的功效，可以证明在突触抑制受损或功能障碍的情况下具有治疗益处。
The activation characteristics of synaptic and extrasynaptic GABA(A) receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7-tetrahydoisoxazolo[5,4-c]pyridin-3(2H)-one (THIP), to further understand the activation profiles of alpha 1 beta 3 gamma 2, alpha 4 beta 3 gamma 2 and alpha 4 beta 3 delta receptors that typify synaptic- and extrasynaptic-type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At delta subunit-containing extrasynaptic-type GABA(A) receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole-cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on alpha 4 beta 3 delta receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic-type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional.