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PMID: 12873381 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Neuron ·Vol. 39 ·No. 2 ·2003-07-17 ·Pages 227-39

Tang TS, Tu H, Chan EY, Maximov A, Wang Z, Wellington CL, Hayden MR, Bezprozvanny I

Abstract

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 Httexp, but not by normal Htt. Transfection of full-length Httexp or caspase-resistant Httexp, 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.

MeSH Terms
Action Potentials/drug effects Animals Blotting, Western Calcium/metabolism Calcium Channels/metabolism Calcium Signaling/physiology Cells, Cultured Cerebellum/metabolism Cerebral Cortex/metabolism Disease Models, Animal Dose-Response Relationship, Drug Drug Interactions Fura-2/metabolism Green Fluorescent Proteins Humans Huntingtin Protein Huntington Disease/metabolism Inositol 1,4,5-Trisphosphate/pharmacology Inositol 1,4,5-Trisphosphate Receptors Lipid Bilayers Luminescent Proteins/metabolism Methoxyhydroxyphenylglycol/analogs & derivatives,pharmacology Nerve Tissue Proteins/isolation & purification,metabolism,physiology Neurons/drug effects,metabolism,physiology Nuclear Proteins/metabolism,physiology Patch-Clamp Techniques Peptide Fragments/metabolism Plasmids/metabolism Protein Binding Receptors, Cytoplasmic and Nuclear/metabolism Recombinant Proteins/chemistry,metabolism Time Factors Two-Hybrid System Techniques
Chemicals
Calcium Channels HAP1 protein, human HTT protein, human Hap1 protein, mouse Huntingtin Protein ITPR1 protein, human Inositol 1,4,5-Trisphosphate Receptors Lipid Bilayers Luminescent Proteins Nerve Tissue Proteins Nuclear Proteins Peptide Fragments Receptors, Cytoplasmic and Nuclear Recombinant Proteins Green Fluorescent Proteins Methoxyhydroxyphenylglycol Inositol 1,4,5-Trisphosphate Calcium Fura-2 3,4-dihydroxyphenylglycol
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Tang Tie-Shan
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Tu Huiping
Chan Edmond Y W
Maximov Anton
Wang Zhengnan
Wellington Cheryl L
Hayden Michael R
Bezprozvanny Ilya
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Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
0896-6273
DOI
10.1016/s0896-6273(03)00366-0
Published
2003-07-17
Pages
227-39
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC3220623
Subset
IM
Grants
NINDS NIH HHS · R01 NS038082 · United States
NINDS NIH HHS · R01 NS038082-02 · United States
NINDS NIH HHS · R01 NS38082 · United States
Corrections
CommentIn
PMID: 12873376
External Links
PubMed source DOI: 10.1016/s0896-6273(03)00366-0 PMC Full Text View journal details
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