Jeon Jaepyo, Bu Fan, Sun Guanghua, Tian Jin-Bin, Ting Shun-Ming, Li Jun, Aronowski Jaroslaw, Birnbaumer Lutz, Freichel Marc, Zhu Michael X
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.
Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.
Front Cell Dev Biol. 2021 Jan 8;8:618663. doi: 10.3389/fcell.2020.618663. eCollection 2020.
The seven canonical members of transient receptor potential (TRPC) proteins form cation channels that evoke membrane depolarization and intracellular calcium concentration ([Ca] ) rise, which are not only important for regulating cell function but their deregulation can also lead to cell damage. Recent studies have implicated complex roles of TRPC channels in neurodegenerative diseases including ischemic stroke. Brain ischemia reduces oxygen and glucose supply to neurons, i.e., Oxygen and Glucose Deprivation (OGD), resulting in [Ca] elevation, ion dyshomeostasis, and excitotoxicity, which are also common in many forms of neurodegenerative diseases. Although ionotropic glutamate receptors, e.g., -methyl-D-aspartate receptors, are well established to play roles in excitotoxicity, the contribution of metabotropic glutamate receptors and their downstream effectors, i.e., TRPC channels, should not be neglected. Here, we summarize the current findings about contributions of TRPC channels in neurodegenerative diseases, with a focus on OGD-induced neuronal death and rodent models of cerebral ischemia/reperfusion. TRPC channels play both detrimental and protective roles to neurodegeneration depending on the TRPC subtype and specific pathological conditions involved. When illustrated the mechanisms by which TRPC channels are involved in neuronal survival or death seem differ greatly, implicating diverse and complex regulation. We provide our own data showing that TRPC1/C4/C5, especially TRPC4, may be generally detrimental in OGD and cerebral ischemia/reperfusion. We propose that although TRPC channels significantly contribute to ischemic neuronal death, detailed mechanisms and specific roles of TRPC subtypes in brain injury at different stages of ischemia/reperfusion and in different brain regions need to be carefully and systematically investigated.
瞬时受体电位（TRPC）蛋白的七个典型成员形成阳离子通道，可引起膜去极化和细胞内钙浓度（[Ca] ）升高，这不仅对调节细胞功能很重要，而且其失调也会导致细胞损伤。最近的研究表明TRPC通道在包括缺血性中风在内的神经退行性疾病中具有复杂的作用。脑缺血会减少神经元的氧气和葡萄糖供应，即氧糖剥夺（OGD），导致[Ca] 升高、离子稳态失衡和兴奋性毒性，这些在多种形式的神经退行性疾病中也很常见。尽管离子型谷氨酸受体，例如N-甲基-D-天冬氨酸受体，在兴奋性毒性中发挥作用已得到充分证实，但代谢型谷氨酸受体及其下游效应器即TRPC通道的作用也不应被忽视。在此，我们总结了关于TRPC通道在神经退行性疾病中作用的当前研究结果，重点关注OGD诱导的神经元死亡和脑缺血/再灌注的啮齿动物模型。TRPC通道对神经退行性变既起有害作用也起保护作用，这取决于所涉及的TRPC亚型和特定病理状况。当阐述TRPC通道参与神经元存活或死亡的机制时，似乎差异很大，这意味着存在多样且复杂的调节。我们提供了自己的数据，表明TRPC1/C4/C5，尤其是TRPC4，在OGD和脑缺血/再灌注中可能通常起有害作用。我们提出，尽管TRPC通道对缺血性神经元死亡有显著贡献，但TRPC亚型在缺血/再灌注不同阶段和不同脑区的脑损伤中的详细机制和具体作用需要仔细且系统地研究。
