HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5‐trisphosphate‐induced Ca 2+ release in primary culture of striatal medium spiny neurons

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.