title: Crosstalk between huntingtin and syntaxin 1A regulates N-type calcium channels.
abstract: We have identified a novel interaction between huntingtin (htt) and N-type calcium channels, a channel key in coupling calcium influx with synaptic vesicle exocytosis. Htt is a widely expressed 350-kDa cytosolic protein bearing an N-terminal polyglutamine tract. Htt is proteolytically cleaved by calpains and caspases and the resultant htt N-terminal fragments have been proposed to be biologically active; however, the cellular function of htt and/or the htt fragments remains enigmatic. We show that N-terminal fragments of htt (consisting of exon1) and full-length htt associate with the synaptic protein interaction (synprint) region of the N-type calcium channel. Given that synprint has previously been shown to bind syntaxin 1A and that this association elicits inhibition of N-type calcium channels, we tested whether htt(exon1) affects the modulation of these channels. Our data indicate that htt(exon1) enhances calcium influx by blocking syntaxin 1A inhibition of N-type calcium channels and attributes a key role for htt N-terminal fragments in the fine tuning of neurotransmission.
authors.affiliation: Department of Physiology and Biophysics, Hotchkiss Brain Institute, The University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Swayne
authors.forename: Lina
authors.initials: L
authors.lastname: Chen
authors.forename: Shahid
authors.initials: S
authors.lastname: Hameed
authors.forename: Wendy
authors.initials: W
authors.lastname: Barr
authors.forename: Emily
authors.initials: E
authors.lastname: Charlesworth
authors.forename: Michael A
authors.initials: MA
authors.lastname: Colicos
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
authors.forename: Janice E A
authors.initials: JE
authors.lastname: Braun
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics; D050827:Syntaxin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020864:Calcium Channels, N-Type; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; C494214:Stx1a protein, mouse; D050827:Syntaxin 1