Huntingtin and Huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1
Huntingtin and Huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1
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DOI：
10.1016/s0896-6273(03)00366-0
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发表时间：
2003-07-17
期刊：
影响因子：
16.2
通讯作者：
Bezprozvanny, I
中科院分区：
文献类型：
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作者：
Tang, TS;Tu, HP;Bezprozvanny, I
亨廷顿病（HD）是由亨廷顿蛋白（Htt）中的多聚谷氨酰胺扩增（exp）引起的。1型肌醇（1，4，5）-三磷酸受体（InsP（3）R1）是细胞内钙（Call）释放通道，在神经元功能中起重要作用。在与InsP 3R 1羧基末端的酵母双杂交筛选中，我们分离出Htt相关蛋白-1A（HAP 1A）。结果表明，在体外和体内均能形成lnsP（3）R1 -HAP 1A-Htt三元复合物。在平面脂质双层重建实验中，InsP（3）R1被InsP（3）激活，被Htt（exp）敏化，但不被正常Htt敏化。转染全长Htt（exp）或半胱天冬酶抗性Htt（exp），但不是正常的Htt，到中型多刺纹状体神经元促进Ca 2+释放响应阈值浓度的选择性mGluR 1/5激动剂3，5-DHPG。我们的研究结果确定了Htt和InsP（3）R1介导的神经元Ca 2+信号之间的一种新的分子联系，并为HD患者和小鼠模型中胞质Call信号的紊乱提供了解释。
Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin (Htt). The type 1 inositol (1,4,5)-triphosphate receptor (InsP(3)R1) is an intracellular calcium (Call) release channel that plays an important role in neuronal function. In a yeast two-hybrid screen with the InsP3R1 carboxy terminus, we isolated Htt-associated protein-1A (HAP1A). We show that an lnsP(3)R1 -HAP1A-Htt ternary complex is formed in vitro and in vivo. In planar lipid bilayer reconstitution experiments, InsP(3)R1 activation by InsP(3) is sensitized by Htt(exp), but not by normal Htt. Transfection of full-length Htt(exp) or caspase-resistant Htt(exp), but not normal Htt, into medium spiny striatal neurons faciliates Ca2+ release in response to threshold concentrations of the selective mGluR1/5 agonist 3,5-DHPG. Our findings identify a novel molecular link between Htt and InsP(3)R1-mediated neuronal Ca2+ signaling and provide an explanation for the derangement of cytosolic Call signaling in HD patients and mouse models.