Huntingtin and Huntingtin-Associated Protein 1 Influence Neuronal Calcium Signaling Mediated by Inositol-(1,4,5) Triphosphate Receptor Type 1

• Published in: Neuron (Cambridge, Mass.) Mass.), 2003-07, Vol.39 (2), p.227-239
• Main Authors: Tang, Tie-Shan, Tu, Huiping, Chan, Edmond Y.W, Maximov, Anton, Wang, Zhengnan, Wellington, Cheryl L, Hayden, Michael R, Bezprozvanny, Ilya
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Amino acids; Animals; Blotting, Western; Brain research; Calcium - metabolism; Calcium Channels - metabolism; Calcium Signaling - physiology; Cells, Cultured; Cerebellum - metabolism; Cerebral Cortex - metabolism; Cloning; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Experiments; Fura-2 - metabolism; Green Fluorescent Proteins; Humans; Huntingtin Protein; Huntington Disease - metabolism; Huntingtons disease; Inositol 1,4,5-Trisphosphate - pharmacology; Inositol 1,4,5-Trisphosphate Receptors; Kinases; Libraries; Lipid Bilayers; Luminescent Proteins - metabolism; Medical research; Methoxyhydroxyphenylglycol - analogs & derivatives; Methoxyhydroxyphenylglycol - pharmacology; Nerve Tissue Proteins - isolation & purification; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - physiology; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Patch-Clamp Techniques; Peptide Fragments - metabolism; Plasmids; Plasmids - metabolism; Protein Binding; Proteins; Receptors, Cytoplasmic and Nuclear - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Rodents; Time Factors; Two-Hybrid System Techniques; Yeast
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/S0896-6273(03)00366-0

Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin (Htt). The type 1 inositol (1,4,5)-triphosphate receptor (InsP 3R1) is an intracellular calcium (Ca 2+) release channel that plays an important role in neuronal function. In a yeast two-hybrid screen with the InsP 3R1 carboxy terminus, we isolated Htt-associated protein-1A (HAP1A). We show that an InsP 3R1-HAP1A-Htt ternary complex is formed in vitro and in vivo. In planar lipid bilayer reconstitution experiments, InsP 3R1 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 Ca 2+ 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 3R1-mediated neuronal Ca 2+ signaling and provide an explanation for the derangement of cytosolic Ca 2+ signaling in HD patients and mouse models.