HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca2+ release in primary culture of striatal medium spiny neurons

Tie-Shan Tang, Huiping Tu, Paul C Orban, Edmond Y W Chan, Michael R Hayden, Ilya Bezprozvanny

Research output: Contribution to journalArticle

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Abstract

Huntington's disease is caused by polyglutamine expansion (exp) in huntingtin (Htt). Htt-associated protein-1 (HAP1) was the first identified Htt-binding partner. The type 1 inositol (1,4,5)-trisphosphate receptor (InsP3R1) is an intracellular Ca2+ release channel that plays an important role in neuronal function. Recently, we identified a InsP3R1-HAP1A-Htt ternary complex in the brain and demonstrated that Httexp, but not normal Htt, activates InsP3R1 in bilayers and facilitates InsP3R1-mediated intracellular Ca2+ release in medium spiny striatal neurons [MSN; T.-S. Tang et al. (2003) Neuron, 39, 227-239]. Here we took advantage of mice with targeted disruption of both HAP1 alleles (HAP1 -/-) to investigate the role of HAP1 in functional interactions between Htt and InsP3R1. We determined that: (i) HAP1 is expressed in the MSN; (ii) HAP1A facilitates functional effects of Htt and Htt(exp) on InsP3R1 in planar lipid bilayers; (iii) HAP1 is required for changes in MSN basal Ca2+ levels resulting from Htt or Htt(exp) overexpression; (iv) HAP1 facilitates potentiation of InsP3R1-mediated Ca2+ release by Htt(exp) in mouse MSN. Our present results indicate that HAP1 plays an important role in functional interactions between Htt and InsP3R1.

Original languageEnglish
Pages (from-to)1779–1787
Number of pages9
JournalEuropean Journal of Neuroscience
Volume20
Issue number7
Early online date14 Sep 2004
DOIs
Publication statusPublished - Oct 2004

Fingerprint

Corpus Striatum
Inositol 1,4,5-Trisphosphate
Culture Media
Neurons
Proteins
Inositol 1,4,5-Trisphosphate Receptors
Huntington Disease
Lipid Bilayers
Alleles
Brain

Keywords

  • animals
  • calcium
  • cells, cultured
  • corpus striatum
  • huntington disease
  • inositol 1,4,5-trisphosphate receptors
  • kinetics
  • lipid bilayers
  • membrane glycoproteins
  • membrane transport proteins
  • methoxyhydroxyphenylglycol
  • mice
  • mice, knockout
  • nerve tissue proteins
  • neurons
  • serotonin plasma membrane transport proteins

Cite this

Tang, Tie-Shan ; Tu, Huiping ; Orban, Paul C ; Chan, Edmond Y W ; Hayden, Michael R ; Bezprozvanny, Ilya. / HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca2+ release in primary culture of striatal medium spiny neurons. In: European Journal of Neuroscience. 2004 ; Vol. 20, No. 7. pp. 1779–1787.
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abstract = "Huntington's disease is caused by polyglutamine expansion (exp) in huntingtin (Htt). Htt-associated protein-1 (HAP1) was the first identified Htt-binding partner. The type 1 inositol (1,4,5)-trisphosphate receptor (InsP3R1) is an intracellular Ca2+ release channel that plays an important role in neuronal function. Recently, we identified a InsP3R1-HAP1A-Htt ternary complex in the brain and demonstrated that Httexp, but not normal Htt, activates InsP3R1 in bilayers and facilitates InsP3R1-mediated intracellular Ca2+ release in medium spiny striatal neurons [MSN; T.-S. Tang et al. (2003) Neuron, 39, 227-239]. Here we took advantage of mice with targeted disruption of both HAP1 alleles (HAP1 -/-) to investigate the role of HAP1 in functional interactions between Htt and InsP3R1. We determined that: (i) HAP1 is expressed in the MSN; (ii) HAP1A facilitates functional effects of Htt and Htt(exp) on InsP3R1 in planar lipid bilayers; (iii) HAP1 is required for changes in MSN basal Ca2+ levels resulting from Htt or Htt(exp) overexpression; (iv) HAP1 facilitates potentiation of InsP3R1-mediated Ca2+ release by Htt(exp) in mouse MSN. Our present results indicate that HAP1 plays an important role in functional interactions between Htt and InsP3R1.",
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author = "Tie-Shan Tang and Huiping Tu and Orban, {Paul C} and Chan, {Edmond Y W} and Hayden, {Michael R} and Ilya Bezprozvanny",
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HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca2+ release in primary culture of striatal medium spiny neurons. / Tang, Tie-Shan; Tu, Huiping; Orban, Paul C; Chan, Edmond Y W; Hayden, Michael R; Bezprozvanny, Ilya.

In: European Journal of Neuroscience, Vol. 20, No. 7, 10.2004, p. 1779–1787.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca2+ release in primary culture of striatal medium spiny neurons

AU - Tang, Tie-Shan

AU - Tu, Huiping

AU - Orban, Paul C

AU - Chan, Edmond Y W

AU - Hayden, Michael R

AU - Bezprozvanny, Ilya

PY - 2004/10

Y1 - 2004/10

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AB - Huntington's disease is caused by polyglutamine expansion (exp) in huntingtin (Htt). Htt-associated protein-1 (HAP1) was the first identified Htt-binding partner. The type 1 inositol (1,4,5)-trisphosphate receptor (InsP3R1) is an intracellular Ca2+ release channel that plays an important role in neuronal function. Recently, we identified a InsP3R1-HAP1A-Htt ternary complex in the brain and demonstrated that Httexp, but not normal Htt, activates InsP3R1 in bilayers and facilitates InsP3R1-mediated intracellular Ca2+ release in medium spiny striatal neurons [MSN; T.-S. Tang et al. (2003) Neuron, 39, 227-239]. Here we took advantage of mice with targeted disruption of both HAP1 alleles (HAP1 -/-) to investigate the role of HAP1 in functional interactions between Htt and InsP3R1. We determined that: (i) HAP1 is expressed in the MSN; (ii) HAP1A facilitates functional effects of Htt and Htt(exp) on InsP3R1 in planar lipid bilayers; (iii) HAP1 is required for changes in MSN basal Ca2+ levels resulting from Htt or Htt(exp) overexpression; (iv) HAP1 facilitates potentiation of InsP3R1-mediated Ca2+ release by Htt(exp) in mouse MSN. Our present results indicate that HAP1 plays an important role in functional interactions between Htt and InsP3R1.

KW - animals

KW - calcium

KW - cells, cultured

KW - corpus striatum

KW - huntington disease

KW - inositol 1,4,5-trisphosphate receptors

KW - kinetics

KW - lipid bilayers

KW - membrane glycoproteins

KW - membrane transport proteins

KW - methoxyhydroxyphenylglycol

KW - mice

KW - mice, knockout

KW - nerve tissue proteins

KW - neurons

KW - serotonin plasma membrane transport proteins

U2 - 10.1111/j.1460-9568.2004.03633.x

DO - 10.1111/j.1460-9568.2004.03633.x

M3 - Article

VL - 20

SP - 1779

EP - 1787

JO - European Journal of Neuroscience

JF - European Journal of Neuroscience

SN - 0953-816X

IS - 7

ER -