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

• Published in: Neurobiology of aging 2017-07, Vol.55, p.1-10
• Main Authors: Silva, Flavia R, Miranda, Artur S, Santos, Rebeca P.M, Olmo, Isabella G, Zamponi, Gerald W, Dobransky, Tomas, Cruz, Jader S, Vieira, Luciene B, Ribeiro, Fabiola M
• Format: Article
• Language: English
• Subjects: BACHD; Glutamate; Gβγ subunits; Huntington's disease; Internal Medicine; N-type Ca2+ channels; Neurology; Syntaxin
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2017.03.015

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 (Cav 2.2), which are essential for presynaptic neurotransmitter release. Thus, to elucidate the mechanism underlying mutant htt-mediated alterations in neurotransmission, we investigated how Cav 2.2 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 WT levels following Cav 2.2 block. Cav 2.2 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 Cav 2.2 and two 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.