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HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5‐trisphosphate‐induced Ca 2+ release in primary culture of striatal medium spiny neurons
Author(s) -
Tang TieShan,
Tu Huiping,
Orban Paul C.,
Chan Edmond Y. W.,
Hayden Michael R.,
Bezprozvanny Ilya
Publication year - 2004
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2004.03633.x
Subject(s) - huntingtin , chemistry , inositol , intracellular , microbiology and biotechnology , mutant , medium spiny neuron , receptor , biology , neuroscience , biochemistry , basal ganglia , central nervous system , gene
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 Ca 2+ 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 Ca 2+ 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 Ca 2+ levels resulting from Htt or Htt exp overexpression; (iv) HAP1 facilitates potentiation of InsP 3 R1‐mediated Ca 2+ 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.