Muscular dystrophy is a family of neuromuscular disorders that is characterized by progressive muscle weakness and wasting. A number of muscular dystrophies are caused by mutations in components of the dystrophin associated protein complex (DAPC). The DAPC plays several different roles including linking the actin cytoskeleton to the extracellular matrix, acting as a membrane organizer for signaling molecules, and regulating calcium homeostasis. Recent evidence indicates that the DAPC is essential for the localization of the calcium-activated BK potassium channel, SLO-1, near calcium channels in the C. elegans muscle. Previously, in a forward genetic screen to identify additional genes responsible for SLO-1 localization and function, we identified
ctn-1, an alpha-catulin homolog with sequence similarity to a-catenin and vinculin. CTN-1 exhibits a punctate expression pattern that closely resembles the pattern of muscle dense bodies.
ctn-1 mutation affects the integrity of the DAPC, since the expression pattern of SGCA-1, a component of the DAPC, is perturbed in
ctn-1 mutants. Consequently, SLO-1 localization was greatly diminished in muscles of
ctn-1 mutants. Thus, CTN-1 uses the DAPC to localize SLO-1 to specific regions of the muscle membrane. In order to further understand the nature of interaction between CTN-1 and the DAPC, we performed yeast two-hybrid interaction studies. Our results indicate that CTN-1 interacts with dystrobrevin (DYB-1), a component of the DAPC that is also known to bind other DAPC components such as dystrophin and syntrophins. Through deletion mapping, we found that the C-terminal region of DYB-1 binds to the N-terminal domain of CTN-1. To further dissect the in vivo role of different domains of CTN-1, we examined expression patterns of GFP-tagged deletion constructs of CTN-1. The characteristic punctate pattern shown by GFP::CTN-1 was not abolished when either the coiled-coil domain, or the N terminal domain of CTN-1 were deleted. However, C-terminal domain deletion resulted in alterations in the punctate pattern. Based on these results, we propose that CTN-1 interacts with the DAPC by binding to DYB-1, thus helping to anchor the DAPC near dense bodies. The DAPC in turn ensures that SLO-1 is localized to regions of the membrane that are rich in calcium channels. It can thus be concluded that a-catulin is an important gene that regulates neuromuscular function and may play a role in the pathogenesis of certain forms of muscular dystrophy.