Crosstalk between huntingtin and syntaxin 1A regulates N-type calcium channels.
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.
Swayne
Leigh Anne
LA
Department of Physiology and Biophysics, Hotchkiss Brain Institute, The University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Chen
Lina
L
Hameed
Shahid
S
Barr
Wendy
W
Charlesworth
Emily
E
Colicos
Michael A
MA
Zamponi
Gerald W
GW
Braun
Janice E A
JE
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*
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