ML297 (VU0456810), the First Potent and Selective Activator of the GIRK Potassium Channel, Displays Antiepileptic Properties in Mice
ML297 (VU0456810), the First Potent and Selective Activator of the GIRK Potassium Channel, Displays Antiepileptic Properties in Mice
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DOI：
10.1021/cn400062a
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发表时间：
2013-09-01
影响因子：
5
通讯作者：
Weaver, C. David
中科院分区：
文献类型：
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作者：
Kaufmann, Kristian;Romaine, Ian;Weaver, C. David
G蛋白激活的内向整流钾（K+）通道（GIRKs）是近二十年来一直是研究热点的离子通道家族（K（ir）3.1-K（ir）3.4）。GIRK由四种不同亚基的各种同源和异源四聚体组合组成。这些亚基以不同的组合在整个中枢神经系统和外周的各种区域中表达。GIRK研究的主体涉及GIRK在控制心律，对奖励/成瘾的影响，对镇痛剂反应的调节等多种过程中的作用。尽管多年的GIRK研究，很少有工具存在选择性地调节GIRK通道活性，直到现在还没有工具存在，有效地和选择性地激活GIRK。在这里，我们报告了第一个真正有效，有效和选择性GIRK激活剂ML 297（VU 0456810）的开发和表征。我们进一步证明了ML 297在两种癫痫体内模型中具有活性，这种疾病中高达40%的患者仍然具有目前治疗难治的症状。ML 297的开发代表了我们选择性探测GIRKs在生理学中作用的能力的真正重大进步，并为开始了解GIRKs作为多种治疗适应症靶点的潜力提供了第一个工具。
The G-protein activated, inward-rectifying potassium (K+) channels, "GIRKs", are a family of ion channels (K(ir)3.1-K(ir)3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo- and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRKs role in physiology as well as providing the first tool for beginning to understand GIRKs potential as a target for a diversity of therapeutic indications.