Inositol 1,4,5-tripshosphate receptor, calcium signalling and Huntington’s disease

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder that has no cure. HD primarily affects medium spiny striatal neurons (MSN). HD is caused by polyglutamine (polyQ) expansion (exp) in the amino-terminal region of a protein huntingtin (Htt). The connection between polyQ expansion in Htt<sup>exp</sup> and MSN neurodegeneration remains elusive. My laboratory discovered that mutant Htt<sup>exp</sup> protein specifically binds to the carboxy-terminal region of the type 1 inositol 1,4,5-trisphosphate receptor (InsP<inf>3</inf>R1), an intracellular Ca<sup>2+</sup> release channel. Moreover, we found that Htt<sup>exp</sup> association with InsP<inf>3</inf>R1 causes sensitization of InsP<inf>3</inf>R1 to activation by InsP<inf>3</inf> in planar lipid bilayers and in primary MSN. Mutant Htt<sup>exp</sup> has also been shown to activate Ca<sup>2+</sup>-permeable NR2B-containing NMDA receptors. All these results suggested that deranged neuronal Ca<sup>2+</sup> signaling may play an important role in pathogenesis of HD. In support of this idea, we demonstrated a connection between abnormal Ca<sup>2+</sup> signaling and apoptosis of MSN cultured from YAC128 HD mouse model. These results indicate that InsP<inf>3</inf>R and other Ca<sup>2+</sup> signaling proteins should be considered as potential therapeutic targets for treatment of HD.

Original languageEnglish (US)
Pages (from-to)323-335
Number of pages13
JournalSub-Cellular Biochemistry
Volume45
StatePublished - 2012

Fingerprint

Calcium-Sensing Receptors
Calcium Signaling
Huntington Disease
Inositol
Corpus Striatum
Neurons
Inositol 1,4,5-Trisphosphate Receptors
Lipid bilayers
Lipid Bilayers
Mutant Proteins
N-Methyl-D-Aspartate Receptors
Neurodegenerative Diseases
Proteins
Chemical activation
Association reactions
Apoptosis
polyglutamine

Keywords

  • Apoptosis
  • Calcium signaling
  • Huntingtin
  • Inositol 1,4,5-trisphosphate
  • Memantine
  • Mitochondria
  • Neurodegeneration
  • NMDA receptor
  • Polyglutamine expansion

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Cancer Research
  • Molecular Biology

Cite this

Inositol 1,4,5-tripshosphate receptor, calcium signalling and Huntington’s disease. / Bezprozvanny, Ilya.

In: Sub-Cellular Biochemistry, Vol. 45, 2012, p. 323-335.

Research output: Contribution to journalArticle

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