Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1

Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin (Htt). The type 1 inositol (1,4,5)-triphosphate receptor (InsP₃R1) is an intracellular calcium (Ca²⁺) release channel that plays an important role in neuronal function. In a yeast two-hybrid screen with the InsP₃R1 carboxy terminus, we isolated Htt-associated protein-1A (HAP1A). We show that an InsP₃R1-HAP1A-Htt ternary complex is formed in vitro and in vivo. In planar lipid bilayer reconstitution experiments, InsP₃R1 activation by InsP₃ is sensitized by Htt^exp, but not by normal Htt. Transfection of full-length Htt^exp or caspase-resistant Htt^exp, but not normal Htt, into medium spiny striatal neurons faciliates Ca²⁺ release in response to threshold concentrations of the selective mGluR1/5 agonist 3,5-DHPG. Our findings identify a novel molecular link between Htt and InsP₃R1-mediated neuronal Ca²⁺ signaling and provide an explanation for the derangement of cytosolic Ca²⁺ signaling in HD patients and mouse models.