N-type Ca2+ channels are affected by full-length mutant huntingtin expression in a mouse model of Huntington's disease

Neurobiol Aging. 2017 Jul:55:1-10. doi: 10.1016/j.neurobiolaging.2017.03.015. Epub 2017 Mar 18.


Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein. In addition to facilitating neurodegeneration, mutant htt is implicated in HD-related alterations of neurotransmission. Previous data showed that htt can modulate N-type voltage-gated Ca2+ channels (Cav2.2), which are essential for presynaptic neurotransmitter release. Thus, to elucidate the mechanism underlying mutant htt-mediated alterations in neurotransmission, we investigated how Cav2.2 is affected by full-length mutant htt expression in a mouse model of HD (BACHD). Our data indicate that young BACHD mice exhibit increased striatal glutamate release, which is reduced to wild type levels following Cav2.2 block. Cav2.2 Ca2+ current-density and plasma membrane expression are increased in BACHD mice, which could account for increased glutamate release. Moreover, mutant htt affects the interaction between Cav2.2 and 2 major channel regulators, namely syntaxin 1A and Gβγ protein. Notably, 12-month old BACHD mice exhibit decreased Cav2.2 cell surface expression and glutamate release, suggesting that Cav2.2 alterations vary according to disease stage.

Keywords: BACHD; G(βγ) subunits; Glutamate; Huntington's disease; N-type Ca(2+) channels; Syntaxin.

MeSH terms

  • Animals
  • Calcium Channels, N-Type / physiology*
  • Disease Models, Animal
  • Glutamates / metabolism
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / physiology*
  • Huntington Disease / genetics*
  • Huntington Disease / physiopathology*
  • Mice, Transgenic
  • Mutation*
  • Neurotransmitter Agents / metabolism
  • Synapses / metabolism
  • Synaptic Transmission / genetics*
  • Syntaxin 1 / physiology


  • Calcium Channels, N-Type
  • Glutamates
  • Htt protein, mouse
  • Huntingtin Protein
  • Neurotransmitter Agents
  • Syntaxin 1