期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 20, 期 7, 页码 1779-1787出版社
WILEY
DOI: 10.1111/j.1460-9568.2004.03633.x
关键词
calcium signalling; HAP1; Huntington's disease; polyglutamine; expansion; knockout mouse
资金
- NINDS NIH HHS [R01 NS38082] Funding Source: Medline
Huntington's disease is caused by polyglutamine expansion (exp) in huntingtin (Htt). Htt-associated protein-1 (HAP1) was the first identified Htt-binding partner. The type 1 inositol (1,4,5)-trisphosphate receptor (InsP(3)R1) is an intracellular Ca2+ release channel that plays an important role in neuronal function. Recently, we identified a InsP(3)R1-HAP1A-Htt ternary complex in the brain and demonstrated that Htt(exp), but not normal Htt, activates InsP(3)R1 in bilayers and facilitates InsP(3)R1-mediated intracellular Ca2+ release in medium spiny striatal neurons [MSN; T.-S. Tang et al. (2003) Neuron, 39, 227-239]. Here we took advantage of mice with targeted disruption of both HAP1 alleles (HAP1 -/-) to investigate the role of HAP1 in functional interactions between Htt and InsP(3)R1. We determined that: (i) HAP1 is expressed in the MSN; (ii) HAP1A facilitates functional effects of Htt and Htt(exp) on InsP(3)R1 in planar lipid bilayers; (iii) HAP1 is required for changes in MSN basal Ca2+ levels resulting from Htt or Htt(exp) overexpression; (iv) HAP1 facilitates potentiation of InsP(3)R1-mediated Ca2+ release by Htt(exp) in mouse MSN. Our present results indicate that HAP1 plays an important role in functional interactions between Htt and InsP(3)R1.
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