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Received July 24, 2001
Accepted after revision November 8, 2001
1 Department of Cellular and Molecular Pharmacology, School of Medicine, University of California, San Francisco, CA 94143-0450, USA
2 Department of Cellular & Molecular Pharmacology, School of Medicine, University of California, San Francisco, CA 94143-0450, USA
* To whom correspondence should be addressed. E-mail: jeffl{at}itsa.ucsf.edu.
We studied the effects of membrane stretch and voltage on the gating of single mechanosensitive (MS) channels in myotubes from dystrophin-deficient mdx mice. In earlier studies of MS channels in mdx myotubes, we found a novel class of stretch-inactivated channels in addition to stretch-activated channels that are also found in wild-type myotubes. In the present experiments, we used a gentle suction protocol to form gigaohm seals on mdx myotubes. This procedure was used to determine whether seal formation damaged the membrane and altered MS channel gating, since dystrophin-deficiency is known to be associated with an increased susceptibility to mechanically induced damage. In some recordings from mdx myotubes, MS channel open probability gradually increased to levels approaching unity following seal formation. In these recordings, channels remained open for the duration of the recording. In other recordings, MS channel open probability remained low after seal formation and applying weak suction evoked conventional stretch-activated gating. Applying strong suction or very positive voltages, however, also caused channels to enter a high open probability gating mode. We found that the shift to a high open probability gating mode was associated with the appearance of stretch-inactivated gating. These findings suggested that mechanical stimulation altered the mechanical properties of the patch causing some MS channels to enter a novel gating mode. In support of this idea, stretch-activated and stretch-inactivated channels were not detected in the same membrane patch and channel inactivation occurred at lower pressures than activation (P1/2, = -13 and -26.5 mmHg, respectively). Other experiments showed that stretch-inactivated gating was not due to a simple loss of MS channel activity from a non-random process such as vesiculation or bleb formation; channel inactivation by suction was readily reversible, stable over tens of minutes, and followed the predictions of the binomial theorem for independent, randomly gating channels. In addition, the voltage-dependent gating of stretch-inactivated channels was similar to that of stretch-activated channels. The results show that MS channels in dystrophin-deficient muscle exist in two distinct gating modes and that mechanical stimuli cause an irreversible conversion between modes. We discuss possible mechanisms for the changes in MS channel gating in relation to the known cytoskeletal abnormalities of mdx muscle and its possible implications for the pathogenesis of Duchenne dystrophy.
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