KCTD12 modulation of GABA(B) receptor function
KCTD12 modulation of GABA(B) receptor function
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DOI：
10.1002/prp2.319
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发表时间：
2017-08-01
影响因子：
2.6
通讯作者：
Petrou, Steven
中科院分区：
文献类型：
--
作者：
Li, Melody;Milligan, Carol J.;Petrou, Steven
天然GABA（B）受体（GABA（B）R）的分子组成和功能多样性仍然知之甚少，因此阻碍了选择性GABA（B）R配体的开发。钾通道四聚化结构域蛋白（KCTD）12是GABA（B）R的辅助亚基，小鼠KCTD 12可改变GABA（B）R的功能。在这项研究中，我们试图表征的影响，人KCTD 12对GABA（B）R的动力学和药理学，使用自动电生理测定。还在KCTD 12敲除小鼠模型中研究了癫痫易感性和乙醇消耗。人KCTD 12共表达改变了GABA（B）R介导的GIRK通道的动力学，加快了激活和脱敏的速率。浓度-响应曲线分析表明，KCTD 12共表达并没有改变激动剂GABA或巴氯芬对GABA（B）R的影响。KCTD 12共表达增强了正变构调节剂CGP 7930的增强作用，以及其对GABA（B）R激活和脱敏的作用。使用KCTD 12敲除小鼠模型检查KCTD 12的体内功能。敲除小鼠对戊四唑促惊厥剂的抵抗力更强，表明癫痫发作的易感性降低。在两瓶偏好测试中，KCTD 12敲除小鼠在高乙醇浓度下表现出消耗减少。总之，人KCTD 12以可能对变构药理学调节敏感的方式加速GABA（B）R的体外动力学。本研究还为KCTD 12与GABA（B）R之间的相互作用具有生理意义，并可能是更有选择性地调节GABA（B）R的机制提供了新的体内证据。
The molecular composition and functional diversity of native GABA(B) receptors (GABA(B)R) are still poorly understood, thus hindering development of selective GABA(B)R ligands. Potassium channel tetramerization domain-containing protein (KCTD) 12 is a GABA(B)R auxiliary subunit and mouse KCTD12 can alter GABA(B)R function. In this study, we sought to characterize the effects of human KCTD12 on GABA(B)R kinetics and pharmacology, using an automated electrophysiological assay. Seizure susceptibility and ethanol consumption were also investigated in a KCTD12 knockout mouse model. Human KCTD12 co-expression altered the kinetics of GABA(B)R-mediated GIRK channels, speeding rates of both activation and desensitization. Analysis of concentration-response curves showed that KCTD12 coexpression did not alter effects of the agonists GABA or baclofen on GABA(B)R. KCTD12 coexpression enhanced the potentiating effects of the positive allosteric modulator CGP7930, and its effects on GABA(B)R activation and desensitization. The function of KCTD12 invivo was examined, using the KCTD12 knockout mouse model. The knockout mice were more resistant to a pentylenetetrazole proconvulsant challenge suggesting reduced seizure susceptibility. In the two bottle preference test, KCTD12 knockout mice demonstrated a reduced consumption at high ethanol concentrations. In summary, human KCTD12 accelerated the kinetics of GABA(B)R invitro, in a manner possibly sensitive to allosteric pharmacological modulation. This study also provides novel invivo evidence that the interaction between KCTD12 and GABA(B)R is of physiological significance, and may be a mechanism to more selectively modulate GABA(B)R.