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Ca²⁺-Mobility in the Sarcoplasmic Reticulum of Ventricular Myocytes Is Low

Pawel Swietach ^*, Kenneth W. Spitzer  and Richard D. Vaughan-Jones ^*

^* Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy, and Genetics, Oxford University, Oxford OX1 3PT, United Kingdom; and Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112-5000

Correspondence: Address reprint requests to Professor Richard D. Vaughan-Jones, PhD, Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy, and Genetics, Oxford University, Oxford OX1 3PT, UK. E-mail: richard.vaughan-jones{at}dpag.ox.ac.uk.

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 (D_CaSR). 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 D_CaSR may actually be low. Here we describe a novel method for measuring D_CaSR. 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 D_CaSR 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 D_CaSR (>40 µm²/s), which may also explain the previous high values. Diffusion-reaction modeling suggests that a low D_CaSR would be sufficient to support local SR Ca²⁺-signaling within sarcomeres during excitation-contraction coupling. Low D_CaSR 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 D_CaSR, may complement the well-established local control of SR Ca²⁺-release by Ca²⁺-channel/ryanodine receptor couplons.

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