The dystrophin complex controls bk channel localization and muscle activity in Caenorhabditis elegans.
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.
Kim
Hongkyun
H
Department of Cell Biology and Anatomy, The Chicago Medical School, Rosalind Franklin University of Science and Medicine, North Chicago, Illinois, United States of America. hongkyun.kim@rosalindfranklin.edu
Pierce-Shimomura
Jonathan T
JT
Oh
Hyun J
HJ
Johnson
Brandon E
BE
Goodman
Miriam B
MB
McIntire
Steven L
SL
D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium; D016189:Dystrophin; D049028:Dystrophin-Associated Protein Complex / Q000502:physiology*; D004594:Electrophysiology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D009132:Muscles / Q000502:physiology*; D050505:Mutant Proteins
D029742:Caenorhabditis elegans Proteins; D016189:Dystrophin; D049028:Dystrophin-Associated Protein Complex; D051036:Large-Conductance Calcium-Activated Potassium Channels; D050505:Mutant Proteins; C494845:slo-1 protein, C elegans; D002118:Calcium