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.

LanguageEnglish
Pages1779–1787
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

T2 - European Journal of Neuroscience

JF - European Journal of Neuroscience

SN - 0953-816X

IS - 7

ER -