Huntingtin and Huntingtin - Associated Protein 1 Influence Neuronal Calcium Signaling Mediated

Only one HAP1 isoform has been identified in humans, and this Vancouver, British Columbia Canada is most similar to rodent HAP1A (Li et al., 1998b). Association of HAP1 with hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) (Li et al., 2002), the p150Glued subunit of dynactin (Engelender et al., 1997; Summary Li et al., 1998a), and the Rac1 guanine nucleotide exchange factor Kalirin-7/Duo (Colomer et al., 1997) has Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin (Htt). The type 1 inositol been discovered in Y2H screens. Targeted disruption of the HAP1 gene in mice results in postnatal death and (1,4,5)-triphosphate receptor (InsP 3 R1) is an intracellu-lar calcium (Ca 2؉) release channel that plays an impor-depressed feeding behavior, suggesting an important role of HAP1 in hypothalamic function (Chan et al., 2002). tant role in neuronal function. In a yeast two-hybrid screen with the InsP 3 R1 carboxy terminus, we isolated Despite all these data, the role of HAP1 in neuronal signaling and the pathogenesis of HD remain unclear Htt-associated protein-1A (HAP1A). We show that an InsP 3 R1-HAP1A-Htt ternary complex is formed in vitro (Bertaux et al., 1998). The inositol (1,4,5)-triphosphate receptor (InsP 3 R) is and in vivo. In planar lipid bilayer reconstitution experiments , InsP 3 R1 activation by InsP 3 is sensitized by an intracellular calcium (Ca 2ϩ) release channel that plays an important role in neuronal Ca 2ϩ signaling (Berridge, Htt exp , but not by normal Htt. Transfection of full-length Htt exp or caspase-resistant Htt exp , but not normal Htt, 1998). Three isoforms of InsP 3 R have been identified (Furuichi et al., 1994). The type 1 receptor (InsP 3 R1) is into medium spiny striatal neurons faciliates Ca 2؉ release in response to threshold concentrations of the the predominant neuronal isoform. Mice lacking InsP 3 R1 display severe ataxic behavior (Matsumoto et al., 1996), selective mGluR1/5 agonist 3,5-DHPG. Our findings identify a novel molecular link between Htt and and mice with a spontaneous mutation in the InsP 3 R1 gene experience convulsions and ataxia (Street et al., InsP 3 R1-mediated neuronal Ca 2؉ signaling and provide an explanation for the derangement of cytosolic Ca 2؉ 1997), suggesting a major role of InsP 3 R1 in neuronal function. To identify novel InsP 3 R1 neuronal binding signaling in HD patients and mouse models. partners, we performed a Y2H screen of a rat …