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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Putative TRP channel antagonists, SKF 96365, flufenamic acid and 2-APB, are non-competitive antagonists at recombinant human α1β2γ2 GABA A receptors
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Putative TRP channel antagonists, SKF 96365, flufenamic acid and 2-APB, are non-competitive antagonists at recombinant human α1β2γ2 GABA A receptors

机译：推定的TRP通道拮抗剂SKF 96365，氟苯那酸和2-APB是重组人α1β2γ2GABA A受体的非竞争性拮抗剂

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Although transient receptor potential (TRP) channel biology research has expanded rapidly in recent years, the field is hampered by the widely held, but relatively poorly investigated, belief that most of the pharmacological tools used to investigate TRP channel function may not be particularly selective for their intended targets. The objective of this study was therefore to determine if this was indeed the case by systematically evaluating the effects of three routinely used putative TRP channel antagonists, SKF 96365, flufenamic acid (FF) and 2-aminoethoxydiphenyl borate (2-APB) against one of the most widely expressed CNS receptor subtypes CNS, the human α1β2γ2 GABA A receptor. Using whole cell patch-clamp recording to record responses to rapidly applied GABA in the absence and presence of the three putative antagonists in turn we found that SKF 96365 (1-100 μM) and FF (1-100 μM) significantly inhibited GABA responses of recombinant human α1β2γ2 GABA A receptor stably expressed in HEK293 cells with IC 50 values of 13.4 ± 5.1 and 1.9 ± 1.4 μM, respectively, suppressing the maximal response to GABA at all concentrations used in a manner consistent with a non-competitive mode of action. SKF 96365 and FF also both significantly reduced desensitisation and prolonged the deactivation kinetics of the receptors to GABA (1 mM; P 0.05). 2-APB (10-1000 μM) also inhibited responses to GABA at all concentrations used with an IC 50 value of 16.7 ± 5.4 μM (n = 3-5) but had no significant effect on the activation, desensitisation or deactivation kinetics of the GABA responses. Taken together this investigation revealed that these widely utilised TRP channel antagonists display significant 'off-target' effects at concentrations that are routinely used for the study of TRP channel function in numerous biological systems and as such, data which is obtained utilising these compounds should be interpreted with caution.
机译：尽管瞬态受体电位（TRP）通道生物学的研究近年来发展迅速，但该领域受到广泛支持，但研究相对较差，因此认为用于研究TRP通道功能的大多数药理学工具可能没有特别的选择他们的预期目标。因此，本研究的目的是通过系统评估三种常规使用的推定的TRP通道拮抗剂，SKF 96365，氟芬那酸（FF）和2-氨基乙氧基二苯基硼酸盐（2-APB）对以下一种的影响，确定是否确实如此表达最广泛的CNS受体亚型CNS是人α1β2γ2GABA A受体。使用全细胞膜片钳记录来依次记录在不存在和存在三种假定拮抗剂的情况下对快速施用的GABA的响应，我们发现SKF 96365（1-100μM）和FF（1-100μM）显着抑制了GABA的响应。重组人α1β2γ2GABA A受体在HEK293细胞中稳定表达，IC 50值分别为13.4±5.1和1.9±1.4μM，以与非竞争性作用方式一致的方式抑制了所有浓度下对GABA的最大反应。 SKF 96365和FF还可显着降低脱敏作用，并延长受体对GABA的失活动力学（1 mM; P <0.05）。 2-APB（10-1000μM）在所有使用浓度下的IC 50值为16.7±5.4μM（n = 3-5）时，也都抑制了对GABA的反应，但对活化，脱敏或失活动力学没有明显影响。 GABA反应。总而言之，这项研究表明，这些广泛使用的TRP通道拮抗剂在许多生物学系统中常规用于研究TRP通道功能的浓度下，显示出明显的“脱靶”效应，因此，使用这些化合物获得的数据应为谨慎解释。

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