Abstract
Genetic defects in the dystrophin-associated protein complex (DAPC) are responsible for a variety of pathological conditions including muscular dystrophy, cardiomyopathy, and vasospasm. Conserved DAPC components from humans to Caenorhabditis elegans suggest a similar molecular function. C. elegans DAPC mutants exhibit a unique locomotory deficit resulting from prolonged muscle excitation and contraction. Here we show that the C. elegans DAPC is essential for proper localization of SLO-1, the large conductance, voltage-, and calcium-dependent potassium (BK) channel, which conducts a major outward rectifying current in muscle under the normal physiological condition. Through analysis of mutants with the same phenotype as the DAPC mutants, we identified the novel islo-1 gene that encodes a protein with two predicted transmembrane domains. We demonstrate that ISLO-1 acts as a novel adapter molecule that links the DAPC to SLO-1 in muscle. We show that a defect in either the DAPC or ISLO-1 disrupts normal SLO-1 localization in muscle. Consistent with observations that SLO-1 requires a high calcium concentration for full activation, we find that SLO-1 is localized near L-type calcium channels in muscle, thereby providing a mechanism coupling calcium influx with the outward rectifying current. Our results indicate that the DAPC modulates muscle excitability by localizing the SLO-1 channel to calcium-rich regions of C. elegans muscle.
Highlights
The dystrophin-associated protein complex (DAPC) is a multimeric protein complex found in the muscle membrane that has been implicated in many degenerative or pathological conditions, including muscular dystrophy, vasospasm and cardiomyopathy [1,2]
Genetic defects in components of this dystrophin complex are responsible for many forms of muscular dystrophy, including Duchenne muscular dystrophy
Accumulating evidence in mammals indicates that dystrophic muscle exhibits an abnormal calcium homeostasis
Summary
The dystrophin-associated protein complex (DAPC) is a multimeric protein complex found in the muscle membrane that has been implicated in many degenerative or pathological conditions, including muscular dystrophy, vasospasm and cardiomyopathy [1,2]. It is clear that dystrophic muscle exhibits abnormal calcium homeostasis and has elevated calcium levels, there is some controversy concerning which ion channels or pumps mediate such calcium increases. Other studies suggest that defects in dystrophin weaken the tight regulation of calcium release from the sarcoplasmic reticulum [4,7] In this case, elevated calcium concentrations may originate from a persistent leak from calcium stores or activation of store-operated channels [7]. It is possible that some of these channels mediate calcium increases in parallel, or that one of them disrupts calcium homeostasis by altering another calcium channel or pump Regardless, none of these prior studies directly link defects in the DAPC to ion channel dysfunction
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