Inhibitory Control Over Ca2+ Sparks via Mechanosensitive Channels Is Disrupted in Dystrophin Deficient Muscle but Restored by Mini-Dystrophin Expression
Figure 10
Proposed model of interactions of mechanosensitive channels (MsC/MsCa) with spontaneous ECRE inhibition in wt muscle and relieved inhibition in mdx muscle during osmotic stress.
In wt muscle, dystrophin expression is linked to suppressed MsC/MsCa activity probably by directly stabilising them to the membrane scaffold under isotonic and hypertonic conditions. The DHPR α1S subunit exerts an inhibitory effect on the RyR1 Mg2+ site via the II–III loop. A direct modulation of this inhibition by mechanosensitive channels is postulated that would not play a major factor in the wt. As a result, under both resting and membrane stress conditions, spontaneous ECRE would be largely suppressed. In the mdx phenotype, stabilisation of MsC/MsCa to the tubule membrane is insufficient in the absence of dystrophin, thus mechanically opening mechanosensitive channels in an aberrantly transducting mode. The putative direct interaction of the latter with the DHPR loop (or other sites) would relief inhibition of the RyR under resting and, more importantly, under membrane stress conditions. ECRE frequency is expected to increase via disinhibited Ca2+ release. Depending on additional Ca2+ influx through mechanosensitive channels under different external Ca2+ containing conditions, peak ECRE frequencies are modulated by Ca2+ dependent downstream activation of NOX/ROS pathways that may directly activate ECRE [51]. SR: sarcoplasmic reticulum. DAG: dystrophin-associated glycoprotein complex.