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Dystrophic muscles get overexcited

Without the SNF-6 acetylcholine transporter (bottom) mutant muscles fall apart. Kim/Macmillan

Loss of adhesion is a primary suspect for the underlying cause of muscular dystrophy (MD). Muscles from individuals with MD look like they are pulling themselves apart, and they are mutant for various members of the dystrophin-glycoprotein complex (DGC), which links intracellular actin to extracellular laminin. But now, Hongkyun Kim, Steven McIntire (University of California, San Francisco, CA), and colleagues suggest that loss of the DGC results in loss of an associated neurotransmitter transporter, thus leading to overexcitation of MD muscles.

Kim was screening for alcohol-resistant worms when he chanced upon the transporter mutants. Like worms mutant for the dystrophin homologue dys-1, the snf-6 mutants bent their heads excessively when they tried to move fast. Wild-type SNF-6 protein promoted uptake of the neurotransmitter acetylcholine into transfected cells, and is needed in muscle cells, presumably to mediate similar uptake.

The snf-6 mutants showed higher neuronal responses downstream of repeated (but not individual) electrical stimuli. Loss of dystrophin or its partner syntrophin resulted in delocalized SNF-6 in older worms, and SNF-6 coimmunoprecipitated with worm syntrophin.

Adhesion may still be important in MD pathology, as the group does not yet know whether all DGC components are in the correct place and functioning properly in the snf-6 mutant. Teasing apart the transporter and adhesion functions may be easier in mammalian systems, although the worm system is still a promising approach for exploring downstream effectors of MD disease.

Reference:

Kim, H., et al. 2004. Nature. 430:891–896.[CrossRef][Medline]

William A. Wells

wellsw{at}rockefeller.edu

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This Article Full Text (PDF, 851K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wells, W. A. Search for Related Content PubMed Articles by Wells, W. A. Social Bookmarking                            What's this?