title: Partial opening and subconductance gating of mechanosensitive ion channels in dystrophic skeletal muscle.
abstract: We recorded the activity of single mechanosensitive (MS) ion channels in skeletal muscle from the mdx mouse, a deletion mutant that lacks the cytoskeletal protein, dystrophin. Experiments were designed to examine the influence of dystrophin, a major component of skeletal muscle costameres, on the behaviour of single MS channels. In the majority of recordings from cell-attached patches, MS channels have a conductance of ∼23 pS. Recordings from some patches, however, showed a smaller conductance channel of ∼7-14 pS. Large and small conductance channels were detected in a single patch and showed serial, non-random gating, suggesting different opening levels of a single channel. Analysis of the distribution of current amplitudes within the open channel showed MS channels fluctuate between subconductance levels. MS channels in dystrophic muscle spend ∼60% of the time at smaller subconductance levels, often failing to reach the fully open level. Applying pressure to the membrane of mdx fibres increases in a graded manner occupancy of the fully open state, while reducing occupancy of subconductance levels. Recordings also show partial openings of MS channels in both wild-type and mdx muscle that fail to reach the fully open state. Partial openings occur at a higher frequency in mdx muscle and reflect occupancy of subconductance levels seen during complete activations. In muscle from mdx/utrn(-/-) double knockout mice, MS channels also spend more time at subconductance levels than the fully open state. Conductance variability of MS channels may represent gating of a heteromeric protein composed of different channel subunits. The results also show that partial opening and prolonged burst duration are distinct mechanisms that contribute to excess Ca(2+) entry in dystrophic muscle.
authors.affiliation: Department of Cellular & Molecular Pharmacology, School of Medicine, University of California, San Francisco, CA 94143-0450, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Vasquez
authors.forename: Nhi
authors.initials: N
authors.lastname: Tan
authors.forename: Mark
authors.initials: M
authors.lastname: Boonyasampant
authors.forename: Kari A
authors.initials: KA
authors.lastname: Koppitch
authors.forename: Jeffry B
authors.initials: JB
authors.lastname: Lansman
mesh_terms: D000818:Animals; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics; D007473:Ion Channels / Q000502:physiology*; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000502:physiology*; D009136:Muscular Dystrophies / Q000503:physiopathology*
chemical_list: D016189:Dystrophin; D007473:Ion Channels