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生理水平的质子在生物体内分布广泛,具有重要的生理功能。在特定的病理条件下,正常的酸碱平衡被破坏,导致质子大量生成和累积,产生对机体有害的酸毒(acidotoxicity)。组织酸化是多种神经系统疾病(如缺血性中风、多发性硬化症以及亨廷顿舞蹈症等)的共同病理特征,也是致这些疾病神经损伤的原因之一。质子可直接激活酸敏感离子通道(acid-sensing ion channel,ASIC),介导组织酸化相关的生理和病理功能,例如,缺血性神经损伤。一直以来,ASIC引起酸毒性神经损伤被认为主要依赖于通道介导的细胞内钙离子升高。然而,本研究组新近的研究表明ASIC1a亚型通道能够通过激活受体相互作用蛋白1(receptor-interacting protein 1,RIP1),介导不依赖于通道离子通透功能的细胞程序性坏死。另外,亚细胞定位研究发现,除了在神经元膜表面,ASIC1a还可以定位在线粒体内膜上,通过调控线粒体通透性转变(mitochondrial permeability transition,MPT)过程,在缺血性神经损伤中发挥重要作用。这些进展使人们对于ASIC介导神经元死亡的机制有了新的认识。
Physiological levels of protons are widely distributed in organisms and have important physiological functions. Under certain pathological conditions, the normal acid-base balance is destroyed, resulting in the formation and accumulation of protons in large quantities, resulting in acidotoxicity that is harmful to the body. Tissue acidification is a common pathological feature of a variety of neurological disorders such as ischemic stroke, multiple sclerosis and Huntington’s disease and is one of the causes of nerve damage to these diseases. Protons can directly activate acid-sensing ion channels (ASICs), mediating the physiological and pathological functions associated with tissue acidification, such as ischemic nerve injury. It has been thought that ASIC-induced acid-induced nerve injury has long been mainly dependent on channel-mediated elevation of intracellular calcium. However, a new study in our group shows that ASIC1a subtype channels mediate programmed cell necrosis independent of channel ion permeability by activating receptor-interacting protein 1 (RIP1). In addition, subcellular localization studies found that, in addition to neuronal membrane surface, ASIC1a can also be located in the mitochondrial inner membrane, by regulating the mitochondrial permeability transition (mitochondrial permeability transition, MPT) process, play an important role in ischemic nerve injury effect. These advances have led to a new understanding of the mechanisms by which ASICs mediate neuronal death.