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

Tie-Shan Tang, Huiping Tu, Edmond Y W Chan, Anton Maximov, Zhengnan Wang, Cheryl L Wellington, Michael R Hayden, Ilya Bezprozvanny

Research output: Contribution to journalArticle

331 Citations (Scopus)

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.

LanguageEnglish
Pages227-239
Number of pages13
JournalNeuron
Volume39
Issue number2
DOIs
Publication statusPublished - 17 Jul 2003

Fingerprint

Inositol 1,4,5-Trisphosphate Receptors
Calcium Signaling
Huntington Disease
Corpus Striatum
Lipid Bilayers
Caspases
Transfection
Yeasts
Calcium
Neurons
Huntingtin Protein
In Vitro Techniques
metabotropic glutamate receptor type 1
polyglutamine
3,5-dihydroxyphenylglycine

Keywords

  • action potentials
  • animals
  • blotting, western
  • calcium
  • calcium channels
  • calcium signaling
  • cells, cultured
  • cerebellum
  • cerebral cortex
  • disease models, animal
  • dose-response relationship, drug
  • drug interactions
  • Fura-2
  • green fluorescent proteins
  • humans
  • Huntington disease
  • inositol 1,4,5-trisphosphate
  • inositol 1,4,5-trisphosphate receptors
  • lipid bilayers
  • luminescent proteins
  • methoxyhydroxyphenylglycol
  • nerve tissue proteins
  • neurons
  • nuclear proteins
  • patch-clamp techniques
  • peptide fragments
  • plasmids
  • protein binding
  • receptors, cytoplasmic and nuclear
  • recombinant proteins
  • time factors
  • two-hybrid system techniques

Cite this

Tang, Tie-Shan ; Tu, Huiping ; Chan, Edmond Y W ; Maximov, Anton ; Wang, Zhengnan ; Wellington, Cheryl L ; Hayden, Michael R ; Bezprozvanny, Ilya. / Huntingtin and Huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. In: Neuron. 2003 ; Vol. 39, No. 2. pp. 227-239.
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title = "Huntingtin and Huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1",
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.",
keywords = "action potentials, animals, blotting, western, calcium, calcium channels, calcium signaling, cells, cultured, cerebellum, cerebral cortex, disease models, animal, dose-response relationship, drug, drug interactions, Fura-2, green fluorescent proteins, humans, Huntington disease, inositol 1,4,5-trisphosphate, inositol 1,4,5-trisphosphate receptors, lipid bilayers, luminescent proteins, methoxyhydroxyphenylglycol, nerve tissue proteins, neurons, nuclear proteins, patch-clamp techniques, peptide fragments, plasmids, protein binding, receptors, cytoplasmic and nuclear, recombinant proteins, time factors, two-hybrid system techniques",
author = "Tie-Shan Tang and Huiping Tu and Chan, {Edmond Y W} and Anton Maximov and Zhengnan Wang and Wellington, {Cheryl L} and Hayden, {Michael R} and Ilya Bezprozvanny",
year = "2003",
month = "7",
day = "17",
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Tang, T-S, Tu, H, Chan, EYW, Maximov, A, Wang, Z, Wellington, CL, Hayden, MR & Bezprozvanny, I 2003, '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, pp. 227-239. https://doi.org/10.1016/S0896-6273(03)00366-0

Huntingtin and Huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. / Tang, Tie-Shan; Tu, Huiping; Chan, Edmond Y W; Maximov, Anton; Wang, Zhengnan; Wellington, Cheryl L; Hayden, Michael R; Bezprozvanny, Ilya.

In: Neuron, Vol. 39, No. 2, 17.07.2003, p. 227-239.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Huntingtin and Huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1

AU - Tang, Tie-Shan

AU - Tu, Huiping

AU - Chan, Edmond Y W

AU - Maximov, Anton

AU - Wang, Zhengnan

AU - Wellington, Cheryl L

AU - Hayden, Michael R

AU - Bezprozvanny, Ilya

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Y1 - 2003/7/17

N2 - 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.

AB - 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.

KW - action potentials

KW - animals

KW - blotting, western

KW - calcium

KW - calcium channels

KW - calcium signaling

KW - cells, cultured

KW - cerebellum

KW - cerebral cortex

KW - disease models, animal

KW - dose-response relationship, drug

KW - drug interactions

KW - Fura-2

KW - green fluorescent proteins

KW - humans

KW - Huntington disease

KW - inositol 1,4,5-trisphosphate

KW - inositol 1,4,5-trisphosphate receptors

KW - lipid bilayers

KW - luminescent proteins

KW - methoxyhydroxyphenylglycol

KW - nerve tissue proteins

KW - neurons

KW - nuclear proteins

KW - patch-clamp techniques

KW - peptide fragments

KW - plasmids

KW - protein binding

KW - receptors, cytoplasmic and nuclear

KW - recombinant proteins

KW - time factors

KW - two-hybrid system techniques

U2 - 10.1016/S0896-6273(03)00366-0

DO - 10.1016/S0896-6273(03)00366-0

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EP - 239

JO - Neuron

T2 - Neuron

JF - Neuron

SN - 0896-6273

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