Departments of Surgery, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Departments of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Acta Pharmacol Sin. 2020 Dec;41(12):1519-1524. doi: 10.1038/s41401-020-00512-4. Epub 2020 Sep 29.
Ion channels are the third largest class of targets for therapeutic drugs. The pharmacology of ion channels is an important research area for identifying new treatment options for human diseases. The past decade or so has seen increasing interest in an ion channel protein belonging to the transient receptor potential (TRP) family, namely the melastatin subfamily member 7 (TRPM7), as an emerging drug target. TRPM7 is a bifunctional protein with a magnesium and calcium-conducting divalent ion channel fused with an active kinase domain. TRPM7 is ubiquitously expressed in human tissues, including the brain, and regulates various cell biology processes such as magnesium and calcium homeostasis, cell growth and proliferation, and embryonic development. TRPM7 provides a link between cellular metabolic status and intracellular calcium homeostasis in neurons due to TRPM7's unique sensitivity to fluctuating intracellular Mg·ATP levels. Thus, the protein plays a key role in ischemic and hypoxic neuronal cell death and brain injury, and is one of the key nonglutamate mechanisms in cerebral ischemia and stroke. Currently, the most potent and specific TRPM7 inhibitor is waixenicin A, a xenicane diterpenoid from the Hawaiian soft coral Sarcothelia edmondsoni. Using waixenicin A as a pharmacological tool, we demonstrated that TRPM7 is involved in promoting neurite outgrowth in vitro. Most recently, we found that waixenicin A reduced hypoxic-ischemic brain injury and preserved long-term behavioral outcomes in mouse neonates. We here suggest that TRPM7 is an emerging drug target for CNS diseases and disorders, and waixenicin A is a viable drug lead for these disorders.
离子通道是治疗药物的第三大类靶点。离子通道药理学是识别人类疾病新治疗方法的重要研究领域。在过去的十年左右，人们对属于瞬时受体电位（TRP）家族的一种离子通道蛋白——即 melastatin 亚家族成员 7（TRPM7）——越来越感兴趣，将其视为一个新兴的药物靶点。TRPM7 是一种具有双重功能的蛋白质，它融合了一个镁和钙导电的二价离子通道和一个活性激酶结构域。TRPM7 在人类组织中广泛表达，包括大脑，并调节各种细胞生物学过程，如镁和钙稳态、细胞生长和增殖以及胚胎发育。由于 TRPM7 对波动的细胞内 Mg·ATP 水平具有独特的敏感性，因此它在神经元中提供了细胞代谢状态和细胞内钙稳态之间的联系。因此，该蛋白在缺血和缺氧性神经元细胞死亡和脑损伤中起着关键作用，是脑缺血和中风中谷氨酸非依赖性机制之一。目前，最有效和最特异的 TRPM7 抑制剂是来自夏威夷软珊瑚 Sarcothelia edmondsoni 的 xenicane 二萜 waixenicin A。我们使用 waixenicin A 作为药理学工具，证明了 TRPM7 参与促进体外神经突生长。最近，我们发现 waixenicin A 可减轻缺氧缺血性脑损伤并改善新生小鼠的长期行为结局。我们在此提出，TRPM7 是 CNS 疾病和障碍的一个新兴药物靶点，而 waixenicin A 是这些疾病的可行药物先导物。
