Utrophin suppresses low frequency oscillations and coupled gating of mechanosensitive ion channels in dystrophic skeletal muscle.
An absence of utrophin in muscle from mdx mice prolongs the open time of single mechanosensitive channels. On a time scale much longer than the duration of individual channel activations, genetic depletion of utrophin produces low frequency oscillations of channel open probability. Oscillatory channel opening occurred in the dystrophin/utrophin mutants, but was absent in wild-type and mdx fibers. By contrast, small conductance channels showed random gating behavior when present in the same patch. Applying a negative pressure to a patch on a DKO fiber produced a burst of mode II activity, but channels subsequently closed and remained silent for tens of seconds during the maintained pressure stimulus. In addition, simultaneous opening of multiple MS channels could be frequently observed in recordings from patches on DKO fibers, but only rarely in wild-type and mdx muscle. A model which accounts for the single-channel data is proposed in which utrophin acts as gating spring which maintains the mechanical stability a caveolar-like compartment. The state of this compartment is suggested to be dynamic; its continuity with the extracellular surface varying over seconds to minutes. Loss of the mechanical stability of this compartment contributes to pathogenic Ca(2+) entry through MS channels in Duchenne dystrophy.
a Department of Cellular and Molecular Pharmacology ; School of Medicine; University of California San Francisco; San Francisco , CA USA.
Jeffry B
JB
Lansman
D000818:Animals; D016189:Dystrophin / Q000235:genetics / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000502:physiology*; D007473:Ion Channels / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology; D009136:Muscular Dystrophies / Q000503:physiopathology; D049411:Utrophin / Q000235:genetics / Q000502:physiology*
D016189:Dystrophin; D007473:Ion Channels; D049411:Utrophin
Duchenne muscular dystrophy; TRPV4; calcium; calcium entry; dystrophin; mechanosensitive channel; muscular dystrophy; skeletal muscle; utrophin