Modulation of Ca2+ release in cultured neonatal rat cardiac myocytes. Insight from subcellular release patterns revealed by confocal microscopy.

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Abstract
It is well established that in heart muscle the influx of Ca2+ through Ca2+ channels during the action potential is the main trigger for Ca2+ release from the sarcoplasmic reticulum (SR), but intact cardiac tissue and single myocytes are also known to exhibit spontaneous Ca2+ release from the SR under a variety of circumstances. Although conditions favoring spontaneous activity have been examined extensively, mechanisms modulating or regulating spontaneous as well as triggered Ca2+ release are still largely unknown. Using the high spatial and temporal resolution of laser-scanning confocal microscopy, we investigated subcellular aspects of spontaneous and triggered Ca2+ release in isolated rat neonatal myocytes loaded with the Ca(2+)-sensitive fluorescent dye fluo 3. Three distinct patterns of spontaneous Ca2+ release were identified: (1) a homogeneous Ca2+ release, presumably corresponding to Ca2+ release during a spontaneous action potential, (2) a focal or spatially restricted Ca2+ release with no or only limited subcellular propagation, and (3) a Ca2+ release propagating as a wave throughout the entire cell. Pharmacologic tools that interfere with the SR revealed that all release types were critically dependent on the Ca2+ release and uptake function of the SR. From our results we conclude that the probability, extent, and pattern of Ca2+ release are modulated on the subcellular level. The observed spectrum of release patterns can be explained by a space- and time-dependent variability in the positive feedback of the Ca(2+)-induced Ca(2+)-release mechanism within an individual myocyte. Presumably, this variability depends on the existence of subcellular functional elements of the SR. The actual degree of positive feedback may be modulated locally by the Ca(2+)-loading state of each SR element.