Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation
Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation
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DOI：
10.1046/j.1471-4159.2003.02020.x
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发表时间：
2003-10-01
影响因子：
4.7
通讯作者：
Schellenberg, GD
中科院分区：
文献类型：
--
作者：
Furukawa, K;Wang, Y;Schellenberg, GD
Tau是一种微管结合蛋白，不仅是阿尔茨海默病神经元缠结的主要成分，而且是与17号染色体（FTDP-17）相关的遗传性额颞叶痴呆和帕金森综合征的致病基因。我们在这里表明，FTDP-17 tau突变（V337 M）在SH-SY 5 Y细胞减少微管聚合，增加电压依赖性钙电流（I-Ca）密度，并减少I-Ca下降。硝苯地平（L型钙通道阻滞剂）显著抑制V337 M降低的I-Ca下降，而ω-芋螺毒素GVIA（N型钙通道阻滞剂）显示较小的影响，表明tau突变影响L型钙通道活性。V337 M tau突变也显著增强了去极化诱导的细胞内钙增加。用微管聚合剂（紫杉醇）、腺苷酸环化酶抑制剂或蛋白激酶A（PKA）抑制剂治疗，抵消了突变tau蛋白对I-Ca的影响。紫杉醇还减弱了表达突变tau的细胞中对去极化的Ca 2+反应。血清剥夺诱导的SH-SY 5 Y细胞凋亡加剧了V337 M突变，硝苯地平，紫杉醇，PKA抑制剂显着保护细胞凋亡。我们的研究结果表明，tau蛋白突变，降低其微管结合能力，增加钙离子内流解聚微管和激活腺苷酸环化酶和PKA。
Tau, a microtubule binding protein, is not only a major component of neurofibrillary tangles in Alzheimer's disease, but also a causative gene for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We show here that an FTDP-17 tau mutation (V337M) in SH-SY5Y cells reduces microtubule polymerization, increases voltage-dependent calcium current (I-Ca) density, and decreases I-Ca rundown. The reduced rundown of I-Ca by V337M was significantly inhibited by nifedipine (L-type Ca channel blocker), whereas omega-conotoxin GVIA (N-type Ca channel blocker) showed smaller effects, indicating that tau mutations affect L-type calcium channel activity. The depolarization-induced increase in intracellular calcium was also significantly augmented by the V337M tau mutation. Treatment with a microtubule polymerizing agent (taxol), an adenylyl cyclase inhibitor, or a protein kinase A (PKA) inhibitor, counteracted the effects of mutant tau on I-Ca. Taxol also attenuated the Ca2+ response to depolarization in cells expressing mutant tau. Apoptosis in SH-SY5Y cells induced by serum deprivation was exacerbated by the V337M mutation, and nifedipine, taxol, and a PKA inhibitor significantly protected cells against apoptosis. Our results indicate that a tau mutation which decreases its microtubule-binding ability augments calcium influx by depolymerizing microtubules and activating adenylyl cyclase and PKA.