L-type calcium channels mediate nicotinic acetylcholine receptor aggregation on cultured myotubes
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PublisherThe University of Arizona.
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AbstractIn this dissertation, I have presented new information on several aspects of the signaling pathway responsible for the clustering of AChRs on muscle cells. First, I have shown that activation of L-CaChs is both necessary for agrin induced clustering of AChRs and sufficient to stimulate AChR clustering even in the absence of agrin. Additionally, I have shown that activation of AChRs causes their own clustering by influencing the activity of L-CaChs. I have also shown that neither AChRs nor L-CaChs play a role in MuSK activation or AChR beta subunit phosphorylation suggesting that the role of AChR and L-CaCh is downstream of MuSK activation and phosphorylation of the AChR beta subunit in the signaling cascade that leads to the aggregation of AChRs. Finally, I have shown that calcium induced clustering and phosphorylation of AChRs require LCaCh activation. These data suggested that although L-CaCh activation is insufficient to cause AChR beta subunit phosphorylation L-CaCh may modulate an intermediate step between MuSK activation and AChR phosphorylation. These data therefore support the hypothesis that L-CaCh activation delivers extracellular calcium to the intracellular machinery that regulates AChR clustering. Furthermore, these data establish the position of L-CaChs in the signaling hierarchy responsible for AChR clustering as being downstream of or parallel to both MuSK activation and AChR phosphorylation in the signaling cascade behind AChR clustering. The data presented in this paper begin to provide an integrated view of NMJ formation in which neuromuscular transmission, calcium signaling, and signaling cascades mediated by neurotrophic factors act in concert to regulate the localization of synaptic molecules to junctional regions of the muscle fiber. Many questions remain, however, regarding the events downstream of MuSK and L-CaCh activation.
Degree ProgramGraduate College
Pharmacology and Toxicology