Desai, Kshipra; (2006) The role of a collybistin-kinesin complex in gephyrin trafficking to inhibitory synapses. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Neurons maintain the fidelity of neurotransmission by accumulating and clustering neurotransmitter receptors at sites precisely opposite presynaptic transmitter release. A long standing question is how this alignment is achieved. One route of investigation is to study the different protein complexes which contribute to the trafficking and localisation of postsynaptic receptors. Gephyrin is a major component of the submembrane scaffold that supports glycine and GABAA receptors at inhibitory synapses. In transfected mammalian cells, gephyrin is translocated to submembrane microaggregates by the GDP-GTP exchange factor collybistin. Three isoforms of rat collybistin have been identified, all of which have a N-terminal SH3 domain and alternative C-termini (CB1, CB2, CBS). The SH3 domain negatively regulates the ability of collybistin to translocate gephyrin to submembranous sites in transfected mammalian cells. Since the majority of native collybistin isoforms appear to harbour the SH3 domain, this suggests that protein-protein interactions or post-translational modifications at the SH3 domain may regulate collybistin activity at specific subcellular locations. The following study was conducted to investigate the mechanisms by which collybistin facilitates gephyrin trafficking and clustering. It was previously suggested that collybistin activated Cdc42, which, in turn, regulated the dynamics of the actin cytoskeleton to facilitate the accumulation of gephyrin and glycine receptors at synapses. One objective of this study was to investigate this proposed role for collybistin. In addition, a library screen conducted to identify collybistin-interacting proteins revealed of a number of proteins involved in intracellular trafficking. These included two kinesin motor proteins - KIF5C and KIF3A, which mediate the intracellular anterograde transport of newly synthesised proteins. The cytoskeleton of neuronal axons and dendrites comprise microtubules, which provide tracks upon which kinesins transport their cargo; collybistin may therefore act as a linker molecule, coupling gephyrin and associated inhibitory receptors to microtubules, via dynamic interactions with kinesins. It is proposed that kinesin, collybistin and gephyrin form an anterograde motor protein complex that delivers GABAA and glycine receptors to inhibitory synapses.

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