Increased Activity of Calcium Leak Channels Caused by Proteolysis Near Sarcolemmal Ruptures |
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Authors: | GC McCarter RA Steinhardt |
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Institution: | (1) Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200 USA, US |
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Abstract: | Dystrophin, a 427 kD membrane-associated structural protein in muscle cells, is thought to confer strength to the myofiber
sarcolemma and protect the membrane from rupture during the stresses of contraction. Dystrophin is absent in muscle cells
from Duchenne muscular dystrophy (DMD) patients and mdx mice, a DMD model. Dystrophic muscle membranes undergo more frequent transient, nonlethal tears than normal cell membranes,
especially during exercise. In addition, the mean open probability of a background (``leak') calcium channel is higher in
dystrophic muscle cells, which leads to higher intracellular free calcium levels. Because elevated calcium levels may contribute
to the eventual necrosis of muscle cells in DMD, we examined the possibility that the history of sarcolemmal rupture at a
specific location on the membrane affects the open probability of nearby calcium leak channels. Membrane ruptures left by
the excision of cell-attached patch-clamp electrodes were used to mimic natural tears. Patches made within 5 microns of excision
sites contained channels with a fourfold greater mean open probability than channels in patches 50 μm away from ruptures.
The increased leak channel activity near ruptures was seen continuously through the duration of the recordings and was not
seen if the rupture was made in the presence of the protease inhibitor leupeptin. Calcium background channels proteolytically
activated near ruptures, perhaps in a calcium-dependent manner, may thus be the lasting consequence of the weaker dystrophic
sarcolemma, leading to chronically raised intracellular free calcium, increased calcium-dependent proteolysis and, eventually,
necrosis.
Received: 29 November 1999/Revised: 13 April 2000 |
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Keywords: | : Myotube — Calcium channel — Proteolysis — Sarcolemma — Muscular dystrophy — Membrane wound |
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