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 (InsP(3)R1) is an intracellular calcium (Call) 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 lnsP(3)R1 -HAP1A-Htt ternary complex is formed in vitro and in vivo. In planar lipid bilayer reconstitution experiments, InsP(3)R1 activation by InsP(3) 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 InsP(3)R1-mediated neuronal Ca2+ signaling and provide an explanation for the derangement of cytosolic Call signaling in HD patients and mouse models.