A Role for Acetylcholine Uptake?

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Science's STKE  24 Aug 2004:
Vol. 2004, Issue 247, pp. tw300
DOI: 10.1126/stke.2472004tw300

Muscular dystrophies, genetic diseases in which muscles become progressively weaker and degenerate, are associated with mutations of the dystrophin-glycoprotein complex (DGC). Although the DGC is believed to maintain muscle structural integrity, the mechanisms through which its dysfunction leads to muscle degeneration have been unclear. Kim et al. observed that mutations in a previously uncharacterized gene produced defects in Caenorhabditis elegans locomotion indistinguishable from those produced by DGC mutations. The authors used genetic mapping, RNA interference, and transgenic rescue to identify the gene as snf-6, previously determined on the basis of amino acid sequence as likely encoding a transporter. When stably transfected into HEK293 cells, SNF-6 mediated sodium-dependent uptake of acetylcholine and choline; moreover, muscles of snf-6 mutants displayed enhanced synaptic currents compared with those of wild-type worms after repetitive nerve stimulation. Pharmacological or genetic inhibition of acetylcholinesterase activity exacerbated the snf-6 mutant phenotype (as previously shown for worms with DGC mutations), whereas the snf-6 phenotype was not influenced by double mutations involving DGC genes. Further, as with DGC mutations, combining snf-6 mutation with mutation of hlh-1, a muscle-specific transcription factor, promoted muscle degeneration. Suppressing calcium channel expression attenuated this degeneration. SNF-6 coimmunoprecipitated with STN-1 (syntrophin, which mediates DGC interactions with effectors) and DGC mutations led to loss of a fluorescently labeled SNF-6 reporter from the neuromuscular junction. Thus, disruption of SNF-6-mediated acetylcholine uptake appears to contribute to the muscle degeneration produced by DGC mutations and--under conditions of enhanced synaptic activity--uptake into muscle may play a crucial role in terminating acetylcholine action.

H. Kim, M. J. Rogers, J. E. Richmond, S. L. McIntire, SNF-6 is an acetylcholine transporter interacting with the dystrophin complex in Caenorhabditis elegans. Nature 430, 891-896 (2004). [Online Journal]

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