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theses

The nicotinic acetylcholine receptor (nAChR) is an excitatory neurotransmitter receptor that mediates muscle functioning by forming nAChR-associated, lattice networks. At the neuromuscular junction (NMJ), synaptic and intracellular proteins, notably Agrin, MusK, and rapsyn, ultimately stabilize these highly dense networks. Interestingly, experimental evidence suggests that cholesterol-rich domains, known as lipid rafts, facilitate signaling among Agrin-Musk and rapsyn, and their presence is essential for healthy nAChR clustering. In spite of their importance, the structural and functional mechanisms of lipid domains are currently unknown. Alongside cholesterol, Docosahexaenoic acid omega-3 fatty acids (DHA-PUFAs) are prevalent at the NMJ, correlate with domain formation, and strongly promote neuronal health. In the present study, we computationally explored the role of DHA-PUFAs on nAChR clustering in the presence and absence of lipid domains. Within coarse-grained (CG) model membranes, nAChRs consistently partitioned into flexible, liquid-disordered domains; boundary lipids were rich in DHA-PUFAs regardless of the number of nAChR molecules, but preventing domain formation also reduced the likelihood of these acyl chains aggregating around nAChR. Taken together, our findings suggest that by inducing domain formation in membranes, DHA plays a critical role in the early stages of nAChR oligomerization.

ETD_9007

M.S.

Includes bibliographical references

by Kristen N. Woods

doi:10.7282/T3G1646D

ETD graduate

The author owns the copyright to this work.