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

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50 Citations (Scopus)


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 Htt(exp) on InsP3R1 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 InsP3R1-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 InsP3R1.

Original languageEnglish
Pages (from-to)1779–1787
Number of pages9
JournalEuropean Journal of Neuroscience
Issue number7
Early online date14 Sep 2004
Publication statusPublished - Oct 2004


  • animals
  • calcium
  • cells, cultured
  • corpus striatum
  • huntington disease
  • inositol 1,4,5-trisphosphate receptors
  • kinetics
  • lipid bilayers
  • membrane glycoproteins
  • membrane transport proteins
  • methoxyhydroxyphenylglycol
  • mice
  • mice, knockout
  • nerve tissue proteins
  • neurons
  • serotonin plasma membrane transport proteins

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