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The role of P2Y1̳ nucleotide receptor in agrin-induced AChR aggregation at the neuromuscular junctions

Authors Ling, Karen Kar Yun
Issue Date 2002
Summary The structure and function of a mature neuromuscular junction (NMJ) is maintained by nerve-derived factors and muscular activity. When muscle contracts upon neural stimulation, ATP is co-released with acetylcholine from motor nerve endings. Recent studies indicate that ATP regulates post-synaptic gene expression, such as acetylcholinesterase (AChE) and acetylcholine receptor (AChR), via P2Y1 receptors that co-localize with AChRs at the NMJs. In order to determine the role of ATP and P2Y1 receptor in modulating the post-synaptic specializations, I investigated the role of ATP and its P2Y1 nucleotide receptors in agrin-induced AChR aggregation in cultured myotubes. By adopting drug treatment and over-expression approaches, I demonstrated that ATP and P2Y1 receptor potentiated the agrin-induced AChR aggregation in cultured chick and mouse myotubes, as well as in neuron-muscle co-cultures. These results suggest that the ATP potentiates agrin response through P2Y1 receptors and play role in maintaining the post-synaptic specializations at the NMJs. The molecular events driving through this ATP-mediated potentiation in agrin response was investigated. It has been speculated that the modulation in agrin-mediated AChR re-distribution could involve cytoskeletal reorganization. Whereas RhoA GTPase has been reported to mediate cytoskeleton rearrangement stimulated by ATP and P2Y1 receptors. Therefore, the involvement of RhoA in mediating the ATP-potentiated agrin response was investigated. In cultured myotubes, the stimulation of P2Y1 receptor activates endogenous RhoA, while the over-expression of RhoA and P2Y1 receptor showed further potentiation in the P2Y1 receptor-mediated effect. This result demonstrated that RhoA could serve as a down stream mediator of P2Y1 receptor in potentiating the agrin-induced AChR aggregation. Besides P2Y1 receptors, agrin could also activate RhoA. When constitutively activated RhoA was over-expressed in cultured myotubes, AChR aggregation was induced. By sharing a common down stream signaling molecule, the activation of P2Y1 receptor could possibly cross talk with agrin signaling in mediating AChR aggregation in muscles. These results suggest that ATP serves as a novel trophic factor to affect the post-synaptic apparatus. P2Y1 nucleotide receptor, as one of the subtypes of ATP receptor, is able to potentiate the agrin-induced AChR aggregation during the formation and maintenance of NMJs.
Note Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2002
Language English
Format Thesis
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