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Publication Detail
Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Twelvetrees AE, Yuen EY, Arancibia-Carcamo IL, MacAskill AF, Rostaing P, Lumb MJ, Humbert S, Triller A, Saudou F, Yan Z, Kittler JT
  • Publication date:
    14/01/2010
  • Pagination:
    53, 65
  • Journal:
    Neuron
  • Volume:
    65
  • Issue:
    1
  • Status:
    Published
  • Country:
    United States
  • PII:
    S0896-6273(09)00997-0
  • Language:
    eng
  • Keywords:
    Animals, Cell Membrane, Cells, Cultured, Humans, Huntingtin Protein, Huntington Disease, Kinesin, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Patch-Clamp Techniques, Peptides, Protein Isoforms, Rats, Rats, Sprague-Dawley, Receptors, GABA-A, Synapses, Synaptic Transmission
Abstract
The density of GABA(A) receptors (GABA(A)Rs) at synapses regulates brain excitability, and altered inhibition may contribute to Huntington's disease, which is caused by a polyglutamine repeat in the protein huntingtin. However, the machinery that delivers GABA(A)Rs to synapses is unknown. We demonstrate that GABA(A)Rs are trafficked to synapses by the kinesin family motor protein 5 (KIF5). We identify the adaptor linking the receptors to KIF5 as the huntingtin-associated protein 1 (HAP1). Disrupting the HAP1-KIF5 complex decreases synaptic GABA(A)R number and reduces the amplitude of inhibitory postsynaptic currents. When huntingtin is mutated, as in Huntington's disease, GABA(A)R transport and inhibitory synaptic currents are reduced. Thus, HAP1-KIF5-dependent GABA(A)R trafficking is a fundamental mechanism controlling the strength of synaptic inhibition in the brain. Its disruption by mutant huntingtin may explain some of the defects in brain information processing occurring in Huntington's disease and provides a molecular target for therapeutic approaches.
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