School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK.
School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK.
Sci Rep. 2022 Sep 8;12(1):15231. doi: 10.1038/s41598-022-18648-0.
Accumulation of tau is observed in dementia, with human tau displaying 6 isoforms grouped by whether they display either 3 or 4 C-terminal repeat domains (3R or 4R) and exhibit no (0N), one (1N) or two (2N) N terminal repeats. Overexpression of 4R0N-tau in rat hippocampal slices enhanced the L-type calcium (Ca) current-dependent components of the medium and slow afterhyperpolarizations (AHPs). Overexpression of both 4R0N-tau and 4R2N-tau augmented Ca1.2-mediated L-type currents when expressed in tsA-201 cells, an effect not observed with the third 4R isoform, 4R1N-tau. Current enhancement was only observed when the pore-forming subunit was co-expressed with Caβ3 and not Caβ2a subunits. Non-stationary noise analysis indicated that enhanced Ca channel current arose from a larger number of functional channels. 4R0N-tau and Caβ3 were found to be physically associated by co-immunoprecipitation. In contrast, the 4R1N-tau isoform that did not augment expressed macroscopic L-type Ca current exhibited greatly reduced binding to Caβ3. These data suggest that physical association between tau and the Caβ3 subunit stabilises functional L-type channels in the membrane, increasing channel number and Ca influx. Enhancing the Ca-dependent component of AHPs would produce cognitive impairment that underlie those seen in the early phases of tauopathies.
在痴呆症中观察到 tau 的积累，人类 tau 显示 6 种异构体，根据它们是否显示 3 个或 4 个 C 端重复结构域（3R 或 4R）以及是否表现出无（0N）、一个（1N）或两个（2N）N 端重复结构域进行分组。在大鼠海马切片中过表达 4R0N-tau 增强了 L 型钙（Ca）电流依赖性的中速和慢速后超极化（AHP）的组成部分。在 tsA-201 细胞中表达时，4R0N-tau 和 4R2N-tau 的过表达均增强了 Ca1.2 介导的 L 型电流，而第三种 4R 异构体 4R1N-tau 则没有观察到这种作用。只有当孔形成亚基与 Caβ3 而不是 Caβ2a 亚基共同表达时，才会观察到电流增强。非稳态噪声分析表明，增强的 Ca 通道电流源于更多功能性通道。共免疫沉淀表明，4R0N-tau 和 Caβ3 是物理相关的。相比之下，没有增强表达的宏观 L 型 Ca 电流的 4R1N-tau 异构体与 Caβ3 的结合大大减少。这些数据表明，tau 与 Caβ3 亚基的物理关联稳定了膜中的功能性 L 型通道，增加了通道数量和 Ca 流入。增强 AHP 的 Ca 依赖性成分会导致认知障碍，这是在 tau 病的早期阶段所看到的。
