Excitation-contraction (E-C) coupling in skeletal muscle refers to the process by which membrane depolarization triggers Ca 2+ release (DICR) through the direct interaction of the dihydropyridine receptor (DHPR) in the T-tubule membrane with the type 1 ryanodine receptor (RyR1) in the sarcoplasmic reticulum. In addition to DICR, RyR1 has two other modes of Ca 2+ release: Ca 2+ -induced Ca 2+ release (CICR) and nitric oxide (NO)-induced Ca 2+ release (NICR). While CICR is the predominant mechanism in cardiac muscle, its physiological relevance in skeletal muscle remains controversial. We recently generated CICR-impaired knock-in mice (RyR1-E3896A) and demonstrated that CICR does not serve as an amplification mechanism for DICR. In this study, we examined whether CICR contributes to the amplification of NICR. Primary skeletal muscle myotubes were prepared from wild-type (WT) and RyR1-E3896A mice, loaded with a fluorescent Ca 2+ indicator, and cytosolic Ca 2+ concentrations were monitored using an inverted fluorescence microscope. Application of the NO donor NOC-7 evoked NICR responses in RyR1-E3896A myotubes that were comparable to those observed in WT myotubes. These results suggest that CICR plays only a minor role, if any, in the regulation of NICR in skeletal muscle.
Miki et al. (Sun,) studied this question.