Gerzanich Volodymyr, Woo S Kyoon, Vennekens Rudi, Tsymbalyuk Orest, Ivanova Svetlana, Ivanov Alexander, Geng Zhihua, Chen Zheng, Nilius Bernd, Flockerzi Veit, Freichel Marc, Simard J Marc
Department of Neurosurgery, University of Maryland School of Medicine, 22 South Greene Street, Suite S12D, Baltimore, Maryland 21201-1595, USA.
Nat Med. 2009 Feb;15(2):185-91. doi: 10.1038/nm.1899. Epub 2009 Jan 25.
The role of transient receptor potential M4 (Trpm4), an unusual member of the Trp family of ion channels, is poorly understood. Using rodent models of spinal cord injury, we studied involvement of Trpm4 in the progressive expansion of secondary hemorrhage associated with capillary fragmentation, the most destructive mechanism of secondary injury in the central nervous system. Trpm4 mRNA and protein were abundantly upregulated in capillaries preceding their fragmentation and formation of petechial hemorrhages. Trpm4 expression in vitro rendered COS-7 cells highly susceptible to oncotic swelling and oncotic death following ATP depletion. After spinal cord injury, in vivo gene suppression in rats treated with Trpm4 antisense or in Trpm4(-/-) mice preserved capillary structural integrity, eliminated secondary hemorrhage, yielded a threefold to fivefold reduction in lesion volume and produced a substantial improvement in neurological function. To our knowledge, this is the first example of a Trp channel that must undergo de novo expression for manifestation of central nervous system pathology.
瞬时受体电位M4（Trpm4）作为Trp离子通道家族的一个特殊成员，其作用目前还知之甚少。我们利用脊髓损伤的啮齿动物模型，研究了Trpm4在与毛细血管破裂相关的继发性出血进行性扩大中的作用，毛细血管破裂是中枢神经系统继发性损伤最具破坏性的机制。在毛细血管破裂和瘀点性出血形成之前，Trpm4 mRNA和蛋白在毛细血管中大量上调。体外Trpm4表达使COS-7细胞在ATP耗竭后极易发生渗透性肿胀和渗透性死亡。脊髓损伤后，用Trpm4反义寡核苷酸处理的大鼠或Trpm4基因敲除（Trpm4(-/-)）小鼠体内的基因抑制作用可保持毛细血管结构完整性，消除继发性出血，使损伤体积减少三到五倍，并使神经功能得到显著改善。据我们所知，这是Trp通道中首个必须经历从头表达才能表现出中枢神经系统病理变化的例子。
