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Title: The muscle-type nicotinic acetylcholine receptor in health and disease
Author: Cetin, Hakan
ISNI:       0000 0004 7966 4423
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Myasthenic syndromes are characterised by weakness and increased fatigability due to an impairment of neuromuscular transmission. Autoimmune or genetic factors compromise the function of muscle-type nicotinic acetylcholine receptors (AChRs), which have two isoforms composed of five subunits in muscle - fetal AChRs have a γ- and adult AChRs have an ε-subunit. Rapsyn is another key component of the postsynaptic molecular machinery required for neuromuscular transmission. It directly interacts with AChRs and is required for AChR clustering at the neuromuscular junction (NMJ). The NMJ is one of the most widely studied synapses but there are still aspects of normal NMJ development and function that need to be better understood. In this work, patch clamp experiments on muscle (TE671/CN21) and non-muscle cells (HEK293) were performed to elucidate AChR function under different physiological and pathological conditions. The adult AChR isoform recovered faster from desensitisation compared to the fetal AChR. Rapsyn was shown to induce AChR aggregation in TE671/CN21 and HEK293 cells and facilitated recovery kinetics in both fetal and adult AChRs in the muscle cell line. Rapsyn also increased the sensitivity for myasthenia gravis (MG) sera to inhibit adult AChR currents, and confined current inhibition to sera with AChR autoantibodies only. Finally, the novel αL251R mutation found in a patient with congenital myasthenic syndrome (CMS) was shown to be associated with a voltage-dependent conversion of AChR ion selectivity from cationic to anionic, transforming the receptor into an inhibitory channel. This work provides an evaluation of the functional impact of rapsyn on AChRs and helps to understand better the significance of the developmental switch from the fetal to the adult isoform. The data suggest that rapsyn is important for the analysis of the functional effect of MG sera on AChRs, and show novel functional effects of a new CMS mutation that sheds light on AChR function.
Supervisor: Beeson, David ; Webster, Richard ; Vincent, Angela Sponsor: Nuffield Department of Clinical Neurosciences ; Austrian Science Fund
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available