Delivery of GABAARs to Synapses Is Mediated by HAP1-KIF5 and Disrupted by Mutant Huntingtin

被引：204

作者：

Twelvetrees, Alison E. ^{[1
]}

Yuen, Eunice Y. ^{[2
]}

Arancibia-Carcamo, I. Lorena ^{[1
]}

MacAskill, Andrew F. ^{[1
]}

Rostaing, Philippe ^{[3
]}

Lumb, Michael J. ^{[1
]}

Humbert, Sandrine ^{[4
]}

Triller, Antoine ^{[3
]}

Saudou, Frederic ^{[4
]}

Yan, Zhen ^{[2
]}

Kittler, Josef T. ^{[1
]}

机构：

[1] UCL, Dept Neurosci Physiol & Pharmacol, London WC1E 6BT, England

[2] SUNY Buffalo, Dept Physiol & Biophys, Buffalo, NY 14214 USA

[3] Ecole Normale Super, INSERM, U789, Biol Cellulaire Synapse N&P, F-75005 Paris, France

[4] CNRS, Unite Mixte Rech 146, Inst Curie, Ctr Univ, F-91405 Orsay, France

来源：

NEURON | 2010年 / 65卷 / 01期

基金：

英国医学研究理事会;

关键词：

INHIBITORY SYNAPTIC-TRANSMISSION; RECEPTOR MEMBRANE TRAFFICKING; NMDA RECEPTOR; HIPPOCAMPAL-NEURONS; INTRACELLULAR TRAFFICKING; AXONAL-TRANSPORT; MOUSE MODEL; KINESIN; PROTEIN; DISEASE;

D O I：

10.1016/j.neuron.2009.12.007

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 polyglutannine 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.

引用

页码：53 / 65

页数：13

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