The sarcoplasmic reticulum (SR) in ventricular myocytes contains releasable Ca2+ for activating cellular contraction. Recent measurements of intra-SR (luminal) Ca2+ suggest a high diffusive Ca2+-mobility constant (DCaSR). This could help spatially to unify SR Ca2+-content ([Ca2+]SRT) and standardize Ca2+-release throughout the cell. But measurements of localized depletions of luminal Ca2+ (Ca2+-blinks), associated with local Ca2+-release (Ca2+-sparks), suggest DCaSR may actually be low. Here we describe a novel method for measuring DCaSR. Using a cytoplasmic Ca2+-fluorophore, we estimate regional [Ca2+]SRT from localized, caffeine-induced SR Ca2+-release. Caffeine microperfusion of one end of a guinea pig or rat myocyte diffusively empties the whole SR at a rate indicating DCaSR is 8–9 μm2/s, up to tenfold lower than previous estimates. Ignoring background SR Ca2+-leakage in our measurement protocol produces an artifactually high DCaSR (>40 μm2/s), which may also explain the previous high values. Diffusion-reaction modeling suggests that a low DCaSR would be sufficient to support local SR Ca2+-signaling within sarcomeres during excitation-contraction coupling. Low DCaSR also implies that [Ca2+]SRT may readily become spatially nonuniform, particularly under pathological conditions of spatially nonuniform Ca2+-release. Local control of luminal Ca2+, imposed by low DCaSR, may complement the well-established local control of SR Ca2+-release by Ca2+-channel/ryanodine receptor couplons
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