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The Journal of Neuroscience, May 3, 2006, 26(18):4841-4851; doi:10.1523/JNEUROSCI.2807-05.2006

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Cellular/Molecular
Lipid Rafts Serve as a Signaling Platform for Nicotinic Acetylcholine Receptor Clustering

Dan Zhu, Wen C. Xiong, and Lin Mei

Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics and Department of Neurology, Medical College of Georgia, Augusta, Georgia 30912

Correspondence should be addressed to Lin Mei, Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, CB2803, 1120 15th Street, Augusta, GA 30912. Email: lmei{at}mcg.edu

Agrin, a motoneuron-derived factor, and the muscle-specific receptor tyrosine kinase (MuSK) are essential for the acetylcholine receptor (AChR) clustering at the postjunctional membrane. However, the underlying signaling mechanisms remain poorly defined. We show that agrin stimulates a dynamic translocation of the AChR into lipid rafts-cholesterol and sphingolipid-rich microdomains in the plasma membrane. This follows MuSK partition into lipid rafts and requires its activation. Disruption of lipid rafts inhibits MuSK activation and downstream signaling and AChR clustering in response to agrin. Rapsyn, an intracellular protein necessary for AChR clustering, is located constitutively in lipid rafts, but its interaction with the AChR is inhibited when lipid rafts are perturbed. These results reveal that lipid rafts may regulate AChR clustering by facilitating the agrin/MuSK signaling and the interaction between the receptor and rapsyn, both necessary for AChR clustering and maintenance. These results provide insight into mechanisms of AChR cluster formation.

Key words: lipid rafts; neuromuscular junction; nicotinic acetylcholine receptors; agrin; MuSK; rapsyn

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Received July 7, 2005; revised March 27, 2006; accepted March 28, 2006.

Correspondence should be addressed to Lin Mei, Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, CB2803, 1120 15th Street, Augusta, GA 30912. Email: lmei{at}mcg.edu

This article has been cited by other articles:

				J. E. Baenziger, S. E. Ryan, M. M. Goodreid, N. Q. Vuong, R. M. Sturgeon, and C. J. B. daCosta Lipid Composition Alters Drug Action at the Nicotinic Acetylcholine Receptor Mol. Pharmacol., March 1, 2008; 73(3): 880 - 890. [Abstract] [Full Text] [PDF]

				D. Zhu, Z. Yang, Z. Luo, S. Luo, W. C. Xiong, and L. Mei Muscle-Specific Receptor Tyrosine Kinase Endocytosis in Acetylcholine Receptor Clustering in Response to Agrin J. Neurosci., February 13, 2008; 28(7): 1688 - 1696. [Abstract] [Full Text] [PDF]

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