title: N-type Ca2+channels are affected by full-length mutant huntingtin expression in a mouse model of Huntington's disease.
abstract: 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 Gβγprotein. 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.
authors.affiliation: Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Flavia R
authors.initials: FR
authors.lastname: Silva
authors.affiliation: Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Artur S
authors.initials: AS
authors.lastname: Miranda
authors.affiliation: Departamento de Farmacologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Rebeca P M
authors.initials: RPM
authors.lastname: Santos
authors.affiliation: Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Isabella G
authors.initials: IG
authors.lastname: Olmo
authors.affiliation: Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
authors.affiliation: DB Biotech, Kosice, Slovakia.
authors.forename: Tomas
authors.initials: T
authors.lastname: Dobransky
authors.affiliation: Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Jader S
authors.initials: JS
authors.lastname: Cruz
authors.affiliation: Departamento de Farmacologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Electronic address: lubvieira@icb.ufmg.br.
authors.forename: Luciene B
authors.initials: LB
authors.lastname: Vieira
authors.affiliation: Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Electronic address: fmribeiro@icb.ufmg.br.
authors.forename: Fabiola M
authors.initials: FM
authors.lastname: Ribeiro
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000502:physiology*; D004195:Disease Models, Animal; D005971:Glutamates / Q000378:metabolism; D000071058:Huntingtin Protein / Q000235:genetics* / Q000502:physiology*; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology*; D008822:Mice, Transgenic; D009154:Mutation; D018377:Neurotransmitter Agents / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics*; D050827:Syntaxin 1 / Q000502:physiology
chemical_list: D020864:Calcium Channels, N-Type; D005971:Glutamates; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D018377:Neurotransmitter Agents; D050827:Syntaxin 1
keywords: BACHD; G(βγ) subunits; Glutamate; Huntington's disease; N-type Ca(2+) channels; Syntaxin