HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca²⁺ 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 (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 Htt^exp, 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 InsP₃R1.