Molecular mechanisms of GABA-A receptor trafficking.
Doctoral thesis, UCL (University College London).
Gamma-aminobutyric acid type A receptors (GABA-A receptors) are the main sites of fast synaptic inhibition in the brain. Regulating the numbers of GABA-A receptors at post-synaptic sites is a key mechanism for regulating the strength of inhibitory synaptic transmission. How GABA-A receptors are rapidly transported to synapses is unknown although the trafficking protein huntingtin associated protein 1 (HAP1) is known to regulate surface GABA-A receptor numbers by an uncharacterised mechanism. This study focuses on how HAP1 regulates GABA-A receptor trafficking. This research demonstrates that GABA-A receptors associate with kinesin microtubule motors of the KIF5 family via HAP1, which acts as a kinesin adaptor protein. The interaction of GABA-A receptors with HAP1 and KIF5 is key for the delivery of GABA-A receptors to synapses. Experiments carried out to interfere with the GABA-A receptor/HAP1/KIF5 complex reduced the numbers of GABA-A receptors on the surface of neurons and at synaptic sites. HAP1 is an interaction partner for huntingtin (htt), the protein that when mutated in Huntington’s disease (HD), due to a polyQ expansion in the htt protein, results in toxic functional changes. Htt is shown here to be part of the GABA-A receptor/HAP1/KIF5 trafficking complex and the presence of polyQ-htt reduces GABA-A receptor trafficking, resulting in less GABA-A receptors at synaptic sites. This disrupted GABA-A receptor trafficking may contribute to a molecular explanation of neuronal defects in HD. This work has identified KIF5 dependent transport of GABA-A receptors to synapses as a key mechanism controlling synaptic GABA-A receptor number and the strength of synaptic inhibition under normal conditions, and as a target for pathological disruptions of inhibiton in neurological disease.
|Title:||Molecular mechanisms of GABA-A receptor trafficking|
|Additional information:||Permission for digitisation not received.|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Neuroscience, Physiology and Pharmacology|
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