Robarts Research Institute, University of Western Ontario, London, ON, Canada.
Mol Brain. 2011 Dec 21;4:44. doi: 10.1186/1756-6606-4-44.
Transient receptor potential melastatin 2 (TRPM2) is a calcium permeable non-selective cation channel that functions as a sensor of cellular redox status. Highly expressed within the CNS, we have previously demonstrated the functional expression of these channels in CA1 pyramidal neurons of the hippocampus. Although implicated in oxidative stress-induced neuronal cell death, and potentially in neurodegenerative disease, the physiological role of TRPM2 in the central nervous system is unknown. Interestingly, we have shown that the activation of these channels may be sensitized by co-incident NMDA receptor activation, suggesting a potential contribution of TRPM2 to synaptic transmission. Using hippocampal cultures and slices from TRPM2 null mice we demonstrate that the loss of these channels selectively impairs NMDAR-dependent long-term depression (LTD) while sparing long-term potentiation. Impaired LTD resulted from an inhibition of GSK-3β, through increased phosphorylation, and a reduction in the expression of PSD95 and AMPARs. Notably, LTD could be rescued in TRPM2 null mice by recruitment of GSK-3β signaling following dopamine D2 receptor stimulation. We propose that TRPM2 channels play a key role in hippocampal synaptic plasticity.
瞬时受体电位 melastatin 2（TRPM2）是一种钙渗透性非选择性阳离子通道，作为细胞氧化还原状态的传感器。在中枢神经系统中高度表达，我们之前已经证明了这些通道在海马体 CA1 锥体神经元中的功能表达。尽管 TRPM2 与氧化应激诱导的神经元细胞死亡有关，并且可能与神经退行性疾病有关，但 TRPM2 在中枢神经系统中的生理作用尚不清楚。有趣的是，我们已经表明，这些通道的激活可能通过同时激活 NMDA 受体而变得敏感，这表明 TRPM2 可能对突触传递有潜在贡献。使用来自 TRPM2 缺失小鼠的海马培养物和切片，我们证明这些通道的缺失选择性地损害了 NMDAR 依赖性长时程抑制（LTD），而不损害长时程增强。LTD 的受损是由于 GSK-3β 通过增加磷酸化而被抑制，以及 PSD95 和 AMPARs 的表达减少所致。值得注意的是，通过多巴胺 D2 受体刺激后招募 GSK-3β 信号，TRPM2 缺失小鼠中的 LTD 可以得到挽救。我们提出 TRPM2 通道在海马体突触可塑性中发挥关键作用。
