Journal
NEUROSCIENCE
Volume 138, Issue 1, Pages 123-132Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2005.11.019
Keywords
agrin; neuromuscular junction; lipid rafts; development
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Funding
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R01HD023924] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR015578] Funding Source: NIH RePORTER
- NCRR NIH HHS [P20 RR015578-060002, P20 RR015578] Funding Source: Medline
- NICHD NIH HHS [R01 HD023924, R01 HD023924-17] Funding Source: Medline
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During development of the neuromuscular junction, high densities of acetylcholine receptors accumulate beneath the overlying nerve terminal. A defining feature of mature synapses is the sharp demarcation of acetylcholine receptor density, which is similar to 1000-fold higher in the postsynaptic as compared with the contiguous extrasynaptic muscle membrane. These high densities of receptors accumulate by at least four mechanisms, re-distribution of existing surface receptors, local synthesis of new receptors, decreased turnover of synaptic receptors, and limitation of diffusion of sub-neural, aggregated receptors. The limitation of receptor diffusion within the membrane is likely in part due to the anchoring of acetylcholine receptor complexes to components of the cytoskeleton. Here we have tested the idea that lipid rafts-mobile, cholesterol enriched microdomains within the lipid bilayer-are another mechanism by which acetylcholine receptors are clustered in the postsynaptic apparatus. Using mouse C2C12 cells, a muscle cell line, we show that a carboxy terminal 95 amino acid fragment [C95 (4,8)] of the extracellular matrix molecule agrin that is essential for nerve-induced postsynaptic differentiation, promotes the redistribution of acetylcholine receptors into lipid rafts. Disruption of lipid rafts before agrin treatment largely inhibits de novo agrin-induced acetylcholine receptor clustering. Moreover, mature acetylcholine receptor clusters are destabilized if lipid rafts are disrupted. These results show that lipid rafts are important in both the initial clustering and later stabilization of agrin-induced acetylcholine receptor clusters and also suggest that lipid rafts may contribute to the postsynaptic localization of acetylcholine receptors in vivo. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.
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