HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca2+ release in primary culture of striatal medium spiny neurons

Tie Shan Tang, Huiping Tu, Paul C. Orban, Edmond Y W Chan, Michael R. Hayden, Ilya Bezprozvanny

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

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 (InsP3R1) is an intracellular Ca2+ release channel that plays an important role in neuronal function. Recently, we identified a InsP3R1-HAP1A-Htt ternary complex in the brain and demonstrated that Httexp, but not normal Htt, activates InsP3R1 in bilayers and facilitates InsP3R1-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 InsP3R1. We determined that: (i) HAP1 is expressed in the MSN; (ii) HAP1A facilitates functional effects of Htt and Httexp on InsP3R1 in planar lipid bilayers; (iii) HAP1 is required for changes in MSN basal Ca2+ levels resulting from Htt or Httexp overexpression; (iv) HAP1 facilitates potentiation of InsP3R1-mediated Ca2+ release by Httexp in mouse MSN. Our present results indicate that HAP1 plays an important role in functional interactions between Htt InsP3R1.

Original languageEnglish (US)
Pages (from-to)1779-1787
Number of pages9
JournalEuropean Journal of Neuroscience
Volume20
Issue number7
DOIs
StatePublished - Oct 1 2004

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Keywords

  • Calcium signalling
  • Expansion
  • HAP1
  • Huntington's disease
  • Knockout mouse
  • Polyglutamine

ASJC Scopus subject areas

  • Neuroscience(all)

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